P2x7 modulators

ABSTRACT

The present invention is directed to a compound of Formula (I) or (Ia) The invention also relates to pharmaceutical compositions comprising compounds of Formula (I) or (Ia) and methods comprising administering of compounds of Formula (I) or (Ia) for treating rheumatoid arthritis, osteoarthritis, psoriasis, septic shock, allergic dermatitis, asthma, allergic asthma, mild to severe asthma, steroid resistant asthma, idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease; airway hyper-responsiveness, diseases of the nervous and neuro-immune system, acute and chronic pain states of neuropathic pain, inflammatory pain, spontaneous pain, opioid induced pain, diabetic neuropathy, postherpetic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia, diseases involved with and without neuroinflammation of the central nervous system, mood disorders, major depression, major depressive disorder, treatment resistant depression, bipolar disorder, anxious depression, anxiety, cognition, sleep disorders, multiple sclerosis, epileptic seizures, Parkinson&#39;s disease, schizophrenia, Alzheimer&#39;s disease, Huntington&#39;s disease, autism, spinal cord injury and cerebral ischemia/traumatic brain injury, stress-related disorders, diseases of the cardiovascular, metabolic, gastrointestinal and urogenital systems such as diabetes, diabetes mellitus, thrombosis, irritable bowel syndrome, irritable bowel disease, Crohn&#39;s disease, ischemic heart disease, ischaemia, hypertension, cardiovascular disease, myocardial infarction, and lower urinary tract dysfunction such as incontinence, lower urinary tract syndrome, Polycystic Kidney Disease, Glomerulonephritis, skeletal disorders, osteoporosis, osteopetrosis, and glaucoma, interstitial cystitis, cough, ureteric obstruction, sepsis, Amyotrophic Lateral Sclerosis, Chaga&#39;s Disease,  chlamydia , neuroblastoma, Tuberculosis, and migraine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application No. 61/785,530filed on Mar. 14, 2013.

FIELD OF THE INVENTION

The present invention is related compounds having P2X7 modulatingproperties, pharmaceutical compositions comprising these compounds,chemical processes for preparing these compounds and their use in thetreatment of diseases associated with P2X7 receptor activity in animals,in particular humans.

BACKGROUND OF THE INVENTION

The P2X7 receptor is a ligand-gated ion channel and is present on avariety of cell types, largely those known to be involved in theinflammatory and/or immune process, specifically, macrophages andmonocytes in the periphery and predominantly in glial cells (microgliaand astrocytes) of the CNS. (Duan and Neary, Glia 2006, 54, 738-746;Skaper et al., FASEB J2009, 24, 337-345; Surprenant and North, Annu.Rev. Physiol. 2009, 71, 333-359). Activation of the P2X7 receptor byextracellular nucleotides, in particular adenosine triphosphate, leadsto the release of proinflammatory cytokines IL-1β and IL-18 (Muller, et.al. Am. J. Respir. Cell Mol. Biol. 2011, 44, 456-464), giant cellformation (macrophages/microglial cells), degranulation (mast cells) andL-selectin shedding (lymphocytes) (Ferrari et al., J. Immunol. 2006,176, 3877-3883; Surprenant and North, Annu. Rev. Physiol. 2009, 71,333-359). P2X7 receptors are also located on antigen-presenting cells(keratinocytes, salivary acinar cells (parotid cells)), hepatocytes,erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bonemarrow cells, neurones, and renal mesangial cells.

The importance of P2X7 in the nervous system arises primarily fromexperiments using P2X7 knock out mice. These mice demonstrate the roleof P2X7 in the development and maintenance of pain as these mice wereprotected from the development of both adjuvant-induced inflammatorypain and partial nerve ligation induced neuropathic pain (Chessell etal., Pain 2005, 114, 386-396). In addition P2X7 knock out mice alsoexhibit an anti-depressant phenotype based on reduced immobility inforced swim and tail suspension tests (Basso et al., Behav. Brain Res.2009, 198, 83-90.). Moreover, the P2X7 pathway is linked to the releaseof the pro-inflammatory cytokine, IL-1β, which has been linked toprecipitation of mood disorders in humans (Dantzer, Immunol. AllergyClin. North Am. 2009, 29, 247-264; Capuron and Miller, Pharmacol. Ther.2011, 130, 226-238). In addition, in murine models of Alzheimer'sdisease, P2X7 was upregulated around amyloid plaques indicating a roleof this target in such pathology as well (Parvathenani et al., J. Biol.Chem. 2003, 278, 13309-13317).

In view of the clinical importance of P2X7, the identification ofcompounds that modulate P2X7 receptor function represents an attractiveavenue into the development of new therapeutic agents. Such compoundsare provided herein.

SUMMARY OF THE INVENTION

The invention is directed to the general and preferred embodimentsdefined, respectively, by the independent and dependent claims appendedhereto, which are incorporated by reference herein. One aspect of thisinvention concerns compounds of Formula (I):

wherein:

each R² is independently selected from the group consisting of H, halo,CN, C₁-C₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and perhaloalkoxy;

n is an integer from 0-3;

X is independently selected from the group consisting of H, C₁-C₃ alkyl,C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂;

Y and Z are independently H or CH₃;

R¹ is independently selected from the group consisting of:

R^(e) and R^(f) are H or C₁-C₃ alkyl;

R^(g) is H, F, or perfluoroalkyl;

R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; and R¹ is H orhalo; or

pharmaceutically acceptable salts of compounds of Formula (I).

Another aspect of this invention concerns compounds of Formula (Ia):

wherein:R² is H, halo, C₁₋₃ alkyl, or perhaloalkyl;n is an integer from 0-4;X is H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, perfluoroalkyl, —NH₂, or—N(C₁₋₃alkyl)₂;Y and Z are independently H or C₁₋₃alkyl;R¹ is selected from the group consisting of:

R^(e) and R^(f) are H or C₁₋₃alkyl;R^(g) is H, F, or perfluoroalkyl;R^(h) is H, C₁₋₃alkyl, CH₂CH₂OCH₃ or perfluoroalkyl; andR^(i) is H or halo; orpharmaceutically acceptable salts of compounds of Formula (Ia).

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I) or (Ia), pharmaceutically acceptable prodrugsof compounds of Formula (I) or (Ia), and pharmaceutically activemetabolites of compounds of Formula (I) or (Ia).

In certain embodiments, the compound of Formula (I) or (Ia) is acompound selected from those species described or exemplified in thedetailed description below.

In a further aspect, the invention relates to pharmaceuticalcompositions for treating a disease, disorder, or medical conditionmediated by P2X7 receptor activity, comprising a therapeuticallyeffective amount of at least one compound selected from compounds ofFormula (I) or (Ia), pharmaceutically acceptable salts of compounds ofFormula (I) or (Ia), pharmaceutically acceptable prodrugs of compoundsof Formula (I) or (Ia), and pharmaceutically active metabolites ofFormula (I) or (Ia).

Pharmaceutical compositions according to the invention may furthercomprise one or more pharmaceutically acceptable excipients.

In another aspect, the chemical embodiments of the present invention areuseful as P2X7 receptor modulators. Thus, the invention is directed to amethod for modulating P2X7 receptor activity, including when suchreceptor is in a subject, comprising exposing P2X7 receptor to atherapeutically effective amount of at least one compound selected fromcompounds of Formula (I) or (Ia), pharmaceutically acceptable salts ofcompounds of Formula (I) or (Ia), pharmaceutically acceptable prodrugsof compounds of Formula (I) or (Ia), and pharmaceutically activemetabolites of compounds of Formula (I) or (Ia).

In another aspect, the invention is directed to a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, comprising administeringto the subject in need of such treatment a therapeutically effectiveamount of at least one compound selected from compounds of Formula (I)or (Ia), pharmaceutically acceptable salts of compounds of Formula (I)or (Ia), pharmaceutically acceptable prodrugs of compounds of Formula(I) or (Ia), and pharmaceutically active metabolites of compounds ofFormula (I) or (Ia). Additional embodiments of methods of treatment areset forth in the detailed description.

In another aspect, a method of studying isotopically labeled compoundsin metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H), detection or imaging techniques [such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays, or in radioactive treatment of patients. For example, an ¹⁸F or¹¹C labeled compound may be particularly preferred for PET or SPECTstudies.

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

Additional embodiments of this invention include methods of makingcompounds of Formula (I) or (Ia), pharmaceutically acceptable salts ofcompounds of Formula (I) or (Ia), pharmaceutically acceptable prodrugsof compounds of Formula (I) or (Ia), and pharmaceutically activemetabolites of Formula (I) or (Ia).

DETAILED DESCRIPTION OF THE INVENTION

This invention concerns compounds of Formula (I):

wherein:

-   -   each R² is independently selected from the group consisting of        H, halo, CN, C₁-C₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and        perhaloalkoxy;    -   n is an integer from 0-3;    -   X is independently selected from the group consisting of H,        C₁-C₃ alkyl, C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂;    -   Y and Z are independently H or CH₃;    -   R¹ is independently selected from the group consisting of:

-   -   R^(e) and R^(f) are H or C₁-C₃ alkyl;    -   R^(g) is H, F, or perfluoroalkyl;    -   R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; and        R^(i) is H or halo; or        pharmaceutically acceptable salts of compounds of Formula (I).

Another aspect of this invention concerns compounds of Formula (Ia):

wherein:R² is H, halo, C₁₋₃ alkyl, or perhaloalkyl;n is an integer from 0-4;X is H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, perfluoroalkyl, —NH₂, or—N(C₁₋₃alkyl)₂;Y and Z are independently H or C₁₋₃alkyl;R¹ is selected from the group consisting of:

R^(e) and R^(f) are H or C₁₋₃alkyl;R^(g) is H, F, or perfluoroalkyl;R^(h) is H, C₁₋₃alkyl, CH₂CH₂OCH₃ or perfluoroalkyl; andR^(i) is H or halo; orpharmaceutically acceptable salts of compounds of Formula (Ia).

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R² is halo.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R² is halo and perfluoroalkyl.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 0-3 and 0-4, respectively.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2-3.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 3.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein at least one R² substituent is in the orthoposition.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein at least one R² substituent is in the paraposition.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein at least one R² substituent is in the orthoposition and at least one R² substituent is in the meta position.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein at least one R² substituent is in the orthoposition and at least one R² substituent is in the para position.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R² is Cl or F.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R² is CF₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is CF₃ and R² is Cl.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is F and R² is Cl.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is Cl and R² is Cl or F.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is Cl and is in the ortho positionand R² is CF₃ and is in the meta position.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is Cl and is in the ortho positionand R² is Cl and is in the meta position.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is Cl and is in the ortho positionand R² is Cl and is in the para position.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein n is 2, R² is F and is in the ortho positionand R² is Cl and is in the para position.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y is H.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y is CH₃ or C₁-C₃ alkyl, respectively.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y is CH₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y is H or CH₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Z is H.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Z is CH₃ or C₁-C₃ alkyl, respectively.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Z is CH₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y and Z are H.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y is H and Z is CH₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y is CH₃ and Z is H.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y and Z are CH₃.

An additional embodiment of the invention is a compound of Formula (I),wherein X is H, C₁-C₃ alkyl, C₃ cycloalkyl, or perfluoroalkyl.

An additional embodiment of the invention is a compound of Formula (Ia),wherein X is H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or perfluoroalkyl.

An additional embodiment of the invention is a compound of Formula (I),wherein X is H, C₁-C₃ alkyl or C₃ cycloalkyl.

An additional embodiment of the invention is a compound of Formula (Ia),wherein X is H, C₁-C₄ alkyl or C₃-C₄ cycloalkyl.

An additional embodiment of the invention is a compound of Formula (I),wherein X is H or C₁-C₃ alkyl.

An additional embodiment of the invention is a compound of Formula (Ia),wherein X is H or C₁-C₄ alkyl.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein X is H.

An additional embodiment of the invention is a compound of Formula (I),wherein X is C₁-C₃ alkyl.

An additional embodiment of the invention is a compound of Formula (Ia),wherein X is C₁-C₄ alkyl.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein X is CH₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein X is H or CH₃.

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R¹ is selected from the group consisting of:

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R¹ is selected from the group consisting of:

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R¹ is selected from the group consisting of:

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R¹ is selected from the group consisting of:

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein R^(f) and R^(g) are H and R¹ is

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein X, Y, Z, R^(f) and R^(g) are H, n is 2, R² isin the ortho position and is Cl, R² is in the meta position and is Cland R¹ is

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Y, Z, R^(f) and R^(g) are H, X is CH₃, n is 2,R² is in the ortho position and is Cl, R² is in the meta position and isCF₃ and R¹ is

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Z, R^(f) and R^(g) are H, X and Y are CH₃, n is2, R² is in the ortho position and is Cl, R² is in the meta position andis CF₃ and R¹ is

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Z, R^(f) and R^(g) are H, X and Y are CH₃, n is2, R² is in the ortho position and is Cl, R² is in the para position andis Cl and R¹ is

An additional embodiment of the invention is a compound of Formula (I)or Formula (Ia), wherein Z, R^(f) and R^(g) are H, X and Y are CH₃, n is2, R² is in the ortho position and is F, R² is in the para position andis Cl and R¹ is

An additional embodiment of the invention is a compound selected fromthe group consisting of those presented in Table 1:

TABLE 1 Compounds of Formula (I) or (Ia)7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;4-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-3-methylbenzonitrile;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dimethylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-3-methylphenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-4,5-difluorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-chloro-4-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-isoxazol-4-yl-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Fluoro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;2-Methyl-7-{[2-methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-cyclopropyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(6R)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(6S)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;3-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methylbenzonitrile;(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(2-amino-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(S)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(S)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(R)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,5-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(4-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;((R)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-dichloro-3-fluorophenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(4-(1H-pyrazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone;(4-(1H-1,2,3-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;7-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;(4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;((2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)- yl)methanone(S)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,3-dichloro-4-fluorophenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,4-dimethylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(4-fluoro-2-methylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-fluoro-2-methylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-methylphenyl)methanone;(R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(phenyl)methanone and(2,4-dichlorophenyl)((6R,8S)-2,6,8-trimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone.(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone(R*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone(S*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(R*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(S*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-methoxy-2-methylphenyl)methanone(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(5-methoxypyridin-3-yl)methanone

An additional embodiment of the invention is a compound selected fromthe group consisting of those presented in Table 1A:

TABLE 1A Compounds of Formula (I) or (Ia)7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;4-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-3-methylbenzonitrile;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dimethylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-3-methylphenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-Chloro-4,5-difluorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2-chloro-4-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-isoxazol-4-yl-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Fluoro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;2-Methyl-7-{[2-methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-cyclopropyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(6R)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(6S)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;3-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methylbenzonitrile;(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(2-amino-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)- yl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(S)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(S)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(R)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,5-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(4-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;((R)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,4-dichloro-3-fluorophenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(4-(1H-pyrazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone;(4-(1H-1,2,3-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;7-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine;(4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;(4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;((2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(S)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)- yl)methanone(S)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,3-dichloro-4-fluorophenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,4-dimethylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(4-fluoro-2-methylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-fluoro-2-methylphenyl)methanone;(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-methylphenyl)methanone;(R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone;(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(phenyl)methanone and(2,4-dichlorophenyl)((6R,8S)-2,6,8-trimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone.

An additional embodiment of the invention is a compound selected fromthe group consisting of those presented in Table 1B:

TABLE 1B Selected Compounds(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone(R*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone(S*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(R*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(S*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-methoxy-2-methylphenyl)methanone and(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(5-methoxypyridin-3-yl)methanone

An additional embodiment of the invention is a pharmaceuticalcomposition for treating a disease, disorder or medical conditionmediated by P2X7 activity comprising:

(a) a therapeutically effective amount of a compound of Formula (I):

wherein:

each R² is independently selected from the group consisting of H, halo,CN, C₁-C₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and perhaloalkoxy;

n is an integer from 0-3;

X is independently selected from the group consisting of H, C₁-C₃ alkyl,C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂;

Y and Z are independently H or CH₃;

R¹ is independently selected from the group consisting of:

R^(e) and R^(f) are H or C₁-C₃ alkyl;

R^(g) is H, F, or perfluoroalkyl;

R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; and R^(i) is Hor halo; or

pharmaceutically acceptable salts of compounds of Formula (I); and

(b) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition for treating a disease, disorder or medical conditionmediated by P2X7 activity comprising:

(a) a therapeutically effective amount of a compound of Formula (Ia):

wherein:R² is H, halo, C₁₋₃ alkyl, or perhaloalkyl;n is an integer from 0-4;X is H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, perfluoroalkyl, —NH₂, or—N(C₁₋₃alkyl)₂;Y and Z are independently H or C₁₋₃alkyl;R¹ is selected from the group consisting of:

R^(e) and R^(f) are H or C₁₋₃alkyl;R^(g) is H, F, or perfluoroalkyl;R^(h) is H, C₁₋₃alkyl, CH₂CH₂OCH₃ or perfluoroalkyl; andR^(i) is H or halo; orpharmaceutically acceptable salts of compounds of Formula (Ia) and

(b) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and a therapeutically effective amount of atleast one compound listed in Tables 1, 1A or 1B and at least onepharmaceutically acceptable excipient.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of at least one compound selected from compounds of Formula (I):

wherein:

each R² is independently selected from the group consisting of H, halo,CN, C₁₋₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and perhaloalkoxy;

n is an integer from 0-3;

X is independently selected from the group consisting of H, C₁-C₃ alkyl,C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂;

Y and Z are independently H or CH₃;

R¹ is independently selected from the group consisting of:

R^(e) and R^(f) are H or C₁-C₃ alkyl;

R^(g) is H, F, or perfluoroalkyl;

R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; and R^(i) is Hor halo; or

pharmaceutically acceptable salts of compounds of Formula (I).

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of at least one compound selected from compounds of Formula (Ia):

wherein:R² is H, halo, C₁₋₃ alkyl, or perhaloalkyl;n is an integer from 0-4;X is H, C₁-C₄ alkyl, C₃-C₄ cycloalkyl, perfluoroalkyl, —NH₂, or—N(C₁₋₃alkyl)₂;Y and Z are independently H or C₁₋₃alkyl;R¹ is selected from the group consisting of:

R^(e) and R^(f) are H or C₁₋₃alkyl;R^(g) is H, F, or perfluoroalkyl;R^(h) is H, C₁₋₃alkyl, CH₂CH₂OCH₃ or perfluoroalkyl; andR^(i) is H or halo; orpharmaceutically acceptable salts of compounds of Formula (Ia).

In preferred embodiments of the inventive method, the disease, disorder,or medical condition is selected from: diseases of the autoimmune andinflammatory system such as: rheumatoid arthritis, osteoarthritis,psoriasis, septic shock, allergic dermatitis, asthma, allergic asthma,mild to severe asthma, steroid resistant asthma, idiopathic pulmonaryfibrosis, allergic rhinitis, chronic obstructive pulmonary disease andairway hyper-responsiveness; diseases of the nervous and neuro-immunesystem such as acute and chronic pain states of neuropathic pain,inflammatory pain, spontaneous pain (opioid induced pain, diabeticneuropathy, postherpetic neuralgia, low back pain, chemotherapy-inducedneuropathic pain, fibromyalgia) (Romagnoli, R, et. al., Expert Opin.Ther. Targets, 2008, 12(5), 647-661), and diseases involved with andwithout neuroinflammation of the CNS such as mood disorders (majordepression, major depressive disorder, treatment resistant depression,bipolar disorder, anxious depression, anxiety) (Friedle, S A, et. al.,Recent Patents on CNS Drug Discovery, 2010, 5, 35-45, Romagnoli, R, et.al., Expert Opin. Ther. Targets, 2008, 12(5), 647-661), cognition, sleepdisorders, multiple sclerosis (Sharp A J, et. al., J Neuroinflammation.2008 Aug. 8; 5:33, Oyanguren-Desez O, et. al., Cell Calcium. 2011November; 50(5):468-72, Grygorowicz T, et. al., Neurochem Int. 2010December; 57(7):823-9), epileptic seizures (Engel T, et. al., FASEB J.2012 April; 26(4):1616-28, Kim J E, et. al. Neurol Res. 2009 November;31(9):982-8, Avignone E, et. al., J Neurosci. 2008 Sep. 10;28(37):9133-44), Parkinson's disease (Marcellino D, et. al., J NeuralTransm. 2010 June; 117(6):681-7), schizophrenia, Alzheimer's disease(Diaz-Hernandez J I, et. al., Neurobiol Aging. 2012 August;33(8):1816-28, Delarasse C, J Biol Chem. 2011 Jan. 28; 286(4):2596-606,Sanz J M, et. al., J Immunol. 2009 Apr. 1; 182(7):4378-85), Huntington'sdisease (Díaz-Hernández M, et. Al., FASEB J. 2009 June; 23(6):1893-906),autism, spinal cord injury and cerebral ischemia/traumatic brain injury(Chu K, et. al., J Neuroinflammation. 2012 Apr. 18; 9:69, Arbeloa J, et.al, Neurobiol Dis. 2012 March; 45(3):954-61).

P2X7 antagonism may also be beneficial in several stress-relateddisorders. In addition, P2X7 intervention may be beneficial in diseasesof the cardiovascular, metabolic, gastrointestinal and urogenitalsystems such as diabetes (Arterioscler Thromb Vasc Biol. 2004 July;24(7):1240-5, J Cell Physiol. 2013 January; 228(1):120-9), thrombosis(Furlan-Freguia C, et. al., J Clin Invest. 2011 July; 121(7):2932-44),irritable bowel syndrome, Crohn's disease, ischemic heart disease,hypertension (Ji X, et. al., Am J Physiol Renal Physiol. 2012 October;303(8):F1207-15), myocardial infarction, and lower urinary tractdysfunction such as incontinence. P2X7 antagonism may also present anovel therapeutic strategy for skeletal disorders, namelyosteoporosis/osteopetrosis and may also modulate secretory function ofexocrine glands. It is also hypothesized that blocking P2X7 may also bebeneficial in glaucoma, interstitial cystitis (Martins J P, et. al., BrJ Pharmacol. 2012 January; 165(1):183-96) and lower urinary tractsyndrome (Br J Pharmacol. 2012 January; 165(1):183-96), IBD/IBS (JImmunol. 2011 Aug. 1; 187(3):1467-74. Epub 2011 Jun. 22), Sleep, RA/OA,Cough/COPD/asthma, cardiovascular disease, GN, ureteric obstruction,diabetes mellitus, hypertension, sepsis, ischaemia, Amyotrophic LateralSclerosis, Chaga's Disease, Chlamydia, Neuroblastoma, Tuberculosis,Polycystic Kidney Disease, and migraine.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, wherein the disease,disorder, or medical condition is selected from the group consisting of:rheumatoid arthritis, osteoarthritis, psoriasis, septic shock, allergicdermatitis, asthma, allergic asthma, mild to severe asthma, steroidresistant asthma, idiopathic pulmonary fibrosis, allergic rhinitis,chronic obstructive pulmonary disease (COPD) and airwayhyper-responsiveness; diseases of the nervous and neuro-immune systemsuch as acute and chronic pain states of neuropathic pain, inflammatorypain, spontaneous pain (opioid induced pain, diabetic neuropathy,postherpetic neuralgia, low back pain, chemotherapy-induced neuropathicpain, fibromyalgia); diseases involved with and withoutneuroinflammation of the CNS such as mood disorders (major depression,major depressive disorder, treatment resistant depression, bipolardisorder, anxious depression, anxiety), cognition, sleep disorders,multiple sclerosis, epileptic seizures, Parkinson's disease,schizophrenia, Alzheimer's disease, Huntington's disease, autism, spinalcord injury and cerebral ischemia/traumatic brain injury, stress-relateddisorders; diseases of the cardiovascular, metabolic, gastrointestinaland urogenital systems such as diabetes, diabetes mellitus, thrombosis,irritable bowel syndrome, IBD, Crohn's disease, ischemic heart disease,ischaemia, hypertension, cardiovascular disease, myocardial infarction,and lower urinary tract dysfunction such as incontinence, lower urinarytract syndrome, Polycystic Kidney Disease, Glomerulonephritis, (GN);skeletal disorders, namely osteoporosis/osteopetrosis: and glaucoma,interstitial cystitis, cough, ureteric obstruction, sepsis, AmyotrophicLateral Sclerosis, Chaga's Disease, chlamydia, neuroblastoma,Tuberculosis, and migraine.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity wherein the disease,disorder or medical condition is treatment resistant depression.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. The term C₁-C₃ alkyl as used here refers to astraight- or branched-chain alkyl group having from 1 to 3 carbon atomsin the chain. The term C₁-C₄ alkyl as used here refers to a straight- orbranched-chain alkyl group having from 1 to 4 carbon atoms in the chain.

The term “alkoxy” includes a straight chain or branched alkyl grouphaving from 1 to 6 carbon atoms in the chain with a terminal oxygenlinking the alkyl group to the rest of the molecule. Alkoxy includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and pentoxy. Theterm C₁-C₃ alkoxy as used here refers to a straight- or branched-chainalkyl group having from 1 to 3 carbon atoms in the chain with a terminaloxygen linking the alkyl group to the rest of the molecule. Examples ofa C₁-C₃ alkoxy substituent include for example: methoxy, ethoxy andisopropxy.

The term “cycloalkyl” refers to a saturated carbocycle having from 3 to6 ring atoms per carbocycle. Illustrative examples of cycloalkyl groupsinclude the following entities, in the form of properly bonded moieties:

The term “C₃-C₄ cycloalkyl” as used here refers to a saturatedcarbocycle having from 3 to 4 ring atoms.

A “heterocycloalkyl” refers to a monocyclic ring structure that issaturated and has from 4 to 6 ring atoms per ring structure selectedfrom carbon atoms and one nitrogen atom. Illustrative entities, in theform of properly bonded moieties, include:

The term “aryl” refers to a monocyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) having 6 atoms perring. (Carbon atoms in the aryl groups are sp² hybridized.)

The term “phenyl” represents the following moiety:

The term “heteroaryl” refers to a monocyclic or fused bicyclicheterocycle (ring structure having ring atoms selected from carbon atomsand up to four heteroatoms selected from nitrogen, oxygen, and sulfur)having from 3 to 9 ring atoms per heterocycle. Illustrative examples ofheteroaryl groups include the following entities, in the form ofproperly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, aryl and heterocycloalkyl groups listed or illustrated aboveare not exhaustive, and that additional species within the scope ofthese defined terms may also be selected.

The term “cyano” refers to the group —CN.

The term “halo” represents chloro, fluoro, bromo or iodo.

The term “perhaloalkyl” refers to a straight- or branched-chain alkylgroup having from 1 to 4 carbon atoms in the chain optionallysubstituting hydrogens with halogens. Examples of perhaloalkyl groupsinclude trifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl(CH₂F), pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃),monofluoroethyl (CH₂CH₂F), trifluoroethyl (CH₂CF₃),tetrafluorotrifluoromethylethyl (—CF(CF₃)₂), and groups that in light ofthe ordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples.

The term “perhaloalkoxy” refers to a straight- or branched-chain alkoxygroup having from 1 to 4 carbon atoms in the chain optionallysubstituting hydrogens with halogens. Examples of perhaloalkoxy groupsinclude trifluoromethoxy (OCF₃), difluoromethoxy (OCF₂H),monofluoromethoxy (OCH₂F), momofluoroethoxy (OCH₂CH₂F),pentafluoroethoxy (OCF₂CF₃), tetrafluoroethoxy (OCHFCF₃),trifluoroethoxy (OCH₂CF₃), tetrafluorotrifluoromethylethoxy(—OCF(CF₃)₂), and groups that in light of the ordinary skill in the artand the teachings provided herein would be considered equivalent to anyone of the foregoing examples.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho” (o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment. To furtherclarify the position of substituents on the phenyl ring, the 2 differentortho positions will be designated as ortho and ortho' and the 2different meta positions as meta and meta' as illustrated below.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

The terms “buffered” solution or “buffer” solution are used hereininterchangeably according to their standard meaning. Buffered solutionsare used to control the pH of a medium, and their choice, use, andfunction is known to those of ordinary skill in the art. See, forexample, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry,p. 261, 5^(th) ed. (2005), describing, inter alia, buffer solutions andhow the concentrations of the buffer constituents relate to the pH ofthe buffer. For example, a buffered solution is obtained by adding MgSO₄and NaHCO₃ to a solution in a 10:1 w/w ratio to maintain the pH of thesolution at about 7.5.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers of the compounds of the generalformula, and mixtures thereof, are considered within the scope of theformula. Thus, any formula given herein is intended to represent aracemate, one or more enantiomeric forms, one or more diastereomericforms, one or more atropisomeric forms, and mixtures thereof.Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

Compounds of the invention may also exist as “rotamers,” that is,conformational isomers that occur when the rotation leading to differentconformations is hindered, resulting a rotational energy barrier to beovercome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

Certain examples contain chemical structures that are depicted as anabsolute enantiomer but are intended to indicate enatiopure materialthat is of unknown configuration. In these cases (R*) or (S*) is used inthe name to indicate that the absolute stereochemistry of thecorresponding stereocenter is unknown. Thus, a compound designated as(R*) refers to an enantiopure compound with an absolute configuration ofeither (R) or (S). In cases where the absolute stereochemistry has beenconfirmed, the structures are named using (R) and (S).

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) or (Ia) or pharmaceutically acceptable salts of compoundsof Formula (I) or (Ia) may be obtained as solvates. Solvates includethose formed from the interaction or complexation of compounds of theinvention with one or more solvents, either in solution or as a solid orcrystalline form. In some embodiments, the solvent is water and then thesolvates are hydrates. In addition, certain crystalline forms ofcompounds of Formula (I) or (Ia) or pharmaceutically acceptable salts ofcompounds of Formula (I) or (Ia) may be obtained as co-crystals. Incertain embodiments of the invention, compounds of Formula (I) or (Ia)were obtained in a crystalline form. In other embodiments, crystallineforms of compounds of Formula (I) or (Ia) were cubic in nature. In otherembodiments, pharmaceutically acceptable salts of compounds of Formula(I) or (Ia) were obtained in a crystalline form. In still otherembodiments, compounds of Formula (I) or (Ia) were obtained in one ofseveral polymorphic forms, as a mixture of crystalline forms, as apolymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) or (Ia) convert in solution between one or morecrystalline forms and/or polymorphic forms.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((sol)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent; and R—COO⁻ _((sol)) refers to the dissociated form of thecompound in a solvent, such as the dissociated form of the compound inan aqueous environment, whether such dissociated form derives fromR—COOH, from a salt thereof, or from any other entity that yields R—COO⁻upon dissociation in the medium being considered. In another example, anexpression such as “exposing an entity to compound of formula R—COOH”refers to the exposure of such entity to the form, or forms, of thecompound R—COOH that exists, or exist, in the medium in which suchexposure takes place. In still another example, an expression such as“reacting an entity with a compound of formula R—COOH” refers to thereacting of (a) such entity in the chemically relevant form, or forms,of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I) or (Ia), preferably of those described aboveand of the specific compounds exemplified herein, and methods oftreatment using such salts.

Pharmaceutically acceptable means approved or approvable by a regulatoryagency of Federal or a state government or the corresponding agency incountries other than the United States, or that is listed in the U. S.Pharmcopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly, in humans.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) or (Ia) thatis non-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. It should possess the desiredpharmacological activity of the parent compound. See, generally, G. S.Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient SaltSelection based on Analysis of the Orange Book Database”, J. Med. Chem.,2007, 50:6665-72, S. M. Berge, et al., “Pharmaceutical Salts”, J PharmSci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties,Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich,2002. Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) or (Ia) may possess a sufficiently acidic group,a sufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) or (Ia) contains a basic nitrogen, thedesired pharmaceutically acceptable salt may be prepared by any suitablemethod available in the art, for example, treatment of the free basewith an inorganic acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid,and the like, or with an organic acid, such as acetic acid, phenylaceticacid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleicacid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) or (Ia) is an acid, such as acarboxylic acid or sulfonic acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide,alkaline earth metal hydroxide, any compatible mixture of bases such asthose given as examples herein, and any other base and mixture thereofthat are regarded as equivalents or acceptable substitutes in light ofthe ordinary level of skill in this technology. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asN-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as tromethamine, benzylamines, pyrrolidines,piperidine, morpholine, and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I) or (Ia), and treatment methods employingsuch pharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I) or (Ia)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I) or(Ia). Examples of amino acid residues include the twenty naturallyoccurring amino acids, commonly designated by three letter symbols, aswell as 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) or (Ia)as amides or alkyl esters. Examples of amides include those derived fromammonia, primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) aminesSecondary amines include 5- or 6-membered heterocycloalkyl or heteroarylring moieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and aminogroups may also yield prodrugs. Carbonate derivatives, sulfonate esters,and sulfate esters of hydroxy groups may also provide prodrugs.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group may be an alkyl ester, optionallysubstituted with one or more ether, amine, or carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, is also useful to yield prodrugs. Prodrugs of this typemay be prepared as described in Robinson et al., J Med Chem. 1996, 39(1), 10-18. Free amines can also be derivatized as amides, sulfonamidesor phosphonamides. All of these prodrug moieties may incorporate groupsincluding ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I) or (Ia), which may also beused in the methods of the invention. A “pharmaceutically activemetabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or (Ia) or salt thereof. Prodrugsand active metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini, et al.,J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv DrugRes. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press,1985); and Larsen, Design and Application of Prodrugs, Drug Design andDevelopment (Krogsgaard-Larsen, et al., eds., Harwood AcademicPublishers, 1991).

The compounds of Formula (I) or (Ia) and their pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of the present invention are usefulas modulators of the P2X7 receptor in the methods of the invention. Assuch modulators, the compounds may act as antagonists, agonists, orinverse agonists. The term “modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate the P2X7 receptorexpression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate P2X7 receptor expressionor activity.

The term “treat”, “treatment” or “treating” as used herein is intendedto refer to administration of an active agent or composition of theinvention to a subject for the purpose of affecting a therapeutic orprophylactic benefit through modulation of P2X7 receptor activity.Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition mediated through modulation of P2X7 receptoractivity. The term “subject” refers to a mammalian patient in need ofsuch treatment, such as a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by P2X7 receptor activity, suchas: rheumatoid arthritis, osteoarthritis, psoriasis, septic shock,allergic dermatitis, asthma, allergic asthma, mild to severe asthma,steroid resistant asthma, idiopathic pulmonary fibrosis, allergicrhinitis, chronic obstructive pulmonary disease (COPD) and airwayhyper-responsiveness; diseases of the nervous and neuro-immune systemsuch as acute and chronic pain states of neuropathic pain, inflammatorypain, spontaneous pain (opioid induced pain, diabetic neuropathy,postherpetic neuralgia, low back pain, chemotherapy-induced neuropathicpain, fibromyalgia); diseases involved with and withoutneuroinflammation of the CNS such as mood disorders (major depression,major depressive disorder, treatment resistant depression, bipolardisorder, anxious depression, anxiety), cognition, sleep disorders,multiple sclerosis, epileptic seizures, Parkinson's disease,schizophrenia, Alzheimer's disease, Huntington's disease, autism, spinalcord injury and cerebral ischemia/traumatic brain injury, stress-relateddisorders; diseases of the cardiovascular, metabolic, gastrointestinaland urogenital systems such as diabetes, diabetes mellitus, thrombosis,irritable bowel syndrome, IBD, Crohn's disease, ischemic heart disease,ischaemia, hypertension, cardiovascular disease, myocardial infarction,and lower urinary tract dysfunction such as incontinence, lower urinarytract syndrome, Polycystic Kidney Disease, Glomerulonephritis, (GN);skeletal disorders, namely osteoporosis/osteopetrosis: and glaucoma,interstitial cystitis, cough, ureteric obstruction, sepsis, AmyotrophicLateral Sclerosis, Chaga's Disease, chlamydia, neuroblastoma,Tuberculosis, and migraine.

In treatment methods according to the invention, a therapeuticallyeffective amount of a pharmaceutical agent according to the invention isadministered to a subject suffering from or diagnosed as having such adisease, disorder, or condition. An “effective amount” or“therapeutically effective amount” means an amount or dose sufficient togenerally bring about the desired therapeutic or prophylactic benefit inpatients in need of such treatment for the designated disease, disorder,or condition. Therapeutically effective amounts or doses of thecompounds of the present invention may be ascertained by routine methodssuch as modeling, dose escalation studies or clinical trials, and bytaking into consideration routine factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the compound,the severity and course of the disease, disorder, or condition, thesubject's previous or ongoing therapy, the subject's health status andresponse to drugs, and the judgment of the treating physician. Anexample of a dose is in the range of from about 0.001 to about 200 mg ofcompound per kg of subject's body weight per day, preferably about 0.05to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divideddosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrativerange for a suitable dosage amount is from about 0.05 to about 7 g/day,or about 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may becoadministered separately with an active agent of compounds of Table 1or included with such an agent in a pharmaceutical composition accordingto the invention. In an exemplary embodiment, additional activeingredients are those that are known or discovered to be therapeuticallyeffective in the treatment of conditions, disorders, or diseasesmediated by P2X7 activity, such as another P2X7 modulator or a compoundactive against another target associated with the particular condition,disorder, or disease. The combination may serve to increase efficacy(e.g., by including in the combination a compound potentiating thepotency or effectiveness of an active agent according to the invention),decrease one or more side effects, or decrease the required dose of theactive agent according to the invention.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) a therapeutically effectiveamount of at least one active agent in accordance with the invention;and (b) a pharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I) and/or (Ia). Reactions may beperformed between the melting point and the reflux temperature of thesolvent, and preferably between 0° C. and the reflux temperature of thesolvent. Reactions may be heated employing conventional heating ormicrowave heating. Reactions may also be conducted in sealed pressurevessels above the normal reflux temperature of the solvent.

Synthetic procedures described in the Schemes below are meant todescribe the synthesis of intermediates and general procedures toprepare embodiments of the invention. Variables presented in the schemesare intended to refer to the synthesis described in that scheme.

The group PG represents a protecting group. One skilled in the art willselect the appropriate protecting group compatible with the desiredreactions. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art. Alternatively, it maybe necessary to employ, in the place of the ultimately desiredsubstituent, a suitable group that may be carried through the reactionscheme and replaced as appropriate with the desired substituent. Suchcompounds, precursors, or prodrugs are also within the scope of theinvention. Examples of preferred protecting groups include; carbamates,benzyl and substituted benzyl groups. Especially preferred protectinggroups are; tert-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl,alpha-chloroethoxycarbonyl, benzyl, 4-nitrobenzyl and diphenylmethyl.

Compound IA is converted to Compound II upon treatment for approximately12 hours with the appropriately substituted formamidine hydrochloride,with a base such as NaOEt or NaOMe in a solvent such as EtOH or MeOH ata temperature such as the reflux temperature of said solvent.Alternative conditions which can be used are: an appropriatelysubstituted formamidine hydrochloride, a base such as K₂CO₃ in a solventsuch as MeOH and water; an appropriately substituted guanidine salt,such as the sulfate or carbonate salts, a base such as K₂CO₃ in asolvent such as MeOH and water; an appropriately substituted guanidinesalt, such as the sulfate or carbonate salts, a base such as TEA in asolvent such as tBuOH.

Hydroxy compound II is converted to triflate III through treatment withtriflic anhydride in a solvent such as DCM or DMF at a temperature ofapproximately 0° C. Triflate III is converted to tricycle IV usingcoupling conditions, sometimes known as Suzuki coupling conditions,wherein the following elements are heated for approximately 12 hours toa temperature around 100° C.: triflate III, an aromatic orheteroaromatic boronic ester or an aromatic or heteroaromatic boronicacid, a palladium catalyst such as PdCl₂dppf, a ligand such as dppf anda salt such as K₃PO₄ in a solvent such as dioxane.

Tricycle IV is transformed to final compound V. Initial deprotection ofthe piperdine protecting group is performed using standard conditionssuch as: when PG=Boc, TFA in DCM. The resulting compound (not shown) canthen be coupled to (a) carboxylic acids using VIII (where W is OH) or(b) carboxylic acid chlorides (where W is Cl). The couplings usingcarboxylic acids (VIII, W is OH) are performed using any number of amidebond coupling conditions such as: VIII (W is OH), EDC, HOBt, a base suchas TEA or DIPEA in a solvent such as DCM or DMF; VIII (W is OH), HATU,HOBt, in a base such as TEA or DIPEA in a solvent such as DCM or DMF.The couplings using carboxylic acid chlorides (VIII, W is Cl) areaccomplished using VIII (W is Cl) in the presence of a base such as TEAor DIPEA in a solvent such as DCM or DMF. Chloride VI is converted tocompound VII using the conditions just described. Compound VIII (where Wis OH) is converted to compound VIII (where W is Cl) throughchlorinating conditions for example treating compound VIII (where W isOH) with (COCl)₂ and DMF in a solvent such as DCM.

Hydroxy compound II is converted into chloride VI by heating acombination of the following reagents to a temperature such as thereflux temperature of the solvent: a chlorinating agent such as POCl₃,along with a base such as dimethyl aniline in a solvent such as DCE.Alternatively chloride VI is prepared by treatment of hydroxy compoundII with PPh₃ and CCl₄ at a temperature of about 70° C. for approximately2.5 h.

Chloride VI is converted to compound IV by treatment with a heteroarylor aryldioxaborolane, heteroaryl or aryl boronic ester or a heteroarylor aryl boronic acid with a catalyst such as (Ph₃P)₄Pd, with a base suchas Na₂CO₃ in a solvent such as dioxane with heating for about one hourin a microwave reactor at a temperature of about 150° C. An alternativemethod, designated Method 3-B, for the conversion of VI to IV may beused when R¹ in a N-linked 5-membered ring heterocycle, for example apyrazole or triazole. This method involves the treatment of theNH-heterocycle with a base such as NaH in a solvent such as DMF followedby addition of chloride VI, providing compound IV. Another method,designated Method 3-C, to affect this conversion also uses the N-linked5-membered heterocycle, for example pyrazole or triazole and involvesheating chloride VI, said 5-membered heterocycle, a base such as Hunig'sbase in a solvent such as ACN. An additional method, designated Method3-D, is sometimes known as a Stille coupling method. This involves thereaction of chloride VI, with the appropriate stannane R¹Sn Bu₃,(Ph₃P)₄Pd in a solvent such as dioxane with heating to a temperature ofabout 140° C. C for approximately 90 minutes in a microwave reactor.Chloride VII may also be converted to compound V using the sameconditions described above for the conversion of compound VI to compoundIV.

Compound VI is converted to compound IX through treatment with compoundVIII (where W is OH), EDCI, HOBt, a base such as TEA or DIPEA in asolvent such as DCM or DMF for approximately 12 hours at approximatelyroom temperature. Intermediate IX is then converted to final compound Vusing the same conditions as described above using Method 3-B.

Compound XA, where T is H, PG is CH(CH₃)Ph and Y is CH₃, is preparedthrough the reaction of ethyl levulinate and DL-alpha-methylbenzylaminewith a reducing agent such as Na(OAc)₃BH in a solvent such as DCE orDCM. This compound is converted to compound XA, where T is CH₂CO₂Et, PGis CH(CH₃)Ph and Y is CH₃, and upon treatment with glyoxylic acid ethylester and Na(OAc)₃BH in a solvent such as DCE or DCM. Compound XA, whereT is CH₂CO₂Et, PG is CH(CH₃)Ph and Y is CH₃, is converted to compound IAupon treatment with a base such as KOtBu in a solvent such as toluene orbenzene. Compound XI is converted to XII using the same conditions asdescribed in Scheme I for the conversion of compound IA to compound II.

Compound XIII is prepared by the addition of a nitrogen protecting groupto the appropriate amino acid ester. In the case of compound XIII (whereZ is CH₃), DL-alanine ethyl ester hydrochloride is used. Compound XIII(where Z is CH₃) is converted to compound XIV upon treatment of compoundXIII (where Z is CH₃), methyl-4-oxo-butanoate with a reducing agent suchas Na(OAc)₃BH in a solvent such as DCE or DCM. Compound XIV can beconverted to compound 1 upon treatment of compound XIV with a base suchas K₃CO₃ in a solvent such as toluene.

Compound XV is converted to compound XVI (where R⁵ is R^(e), R^(f) orR^(g)) and where R⁵ is H through deprotection of the protecting group(PG). This compound XVI (where R⁵ is H) is converted to compound XVI(where R⁵ is CH₂CH₂F) upon treatment with 1-bromo-2-fluoroethane in asolvent such as DMF heated to a temperature of about 120° C. forapproximately 10 minutes under microwave irradiation. Compound XVI(where R⁵ is H) is converted to compound XVI (where R⁵ is CH₂CH₂OCH₃)using the same procedure but employing 2-bromoethyl methyl etherCompound XVI (where R⁵ is CH₃) is made from compound XVI (where R⁵ is H)by treatment of said compound with NaH in DMF followed by addition ofMeI.

An intermediate compound,2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Compound XVII, structure not shown) is prepared through the reaction ofPd(dppf)₂Cl₂.HCl, 2-bromo-6-fluoropyridine, bis(pinacolato)diboron, andKOAc in a solvent such as dioxane with heating to a temperature ofapproximately 115° C. for approximately 1 h.

EXAMPLES

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Reactions under microwave irradiation conditions were carriedout in a Biotage Initiator or CEM Discover instrument.

The term R¹Sn Bu₃ is intented to encompass similar stannane reagentssuch as R¹SnMe₃, R¹Sn Ph₃ and the like.

Normal-phase silica gel column chromatography (sgc) was performed onsilica gel (SiO₂) using prepackaged cartridges, eluting with 2 MNH₃/MeOH in CH₂Cl₂ unless otherwise indicated.

Preparative reverse-phase high performance liquid chromatography (HPLC)was performed on a Gilson HPLC with an Xterra Prep RP₁₈ (5 μm, 30×100mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH₄OH)over 12 to 18 min, and a flow rate of 30 mL/min.

Compounds obtained as HCl salts were prepared by the addition of 1 M HClin diethyl ether to a CH₂Cl₂ solution of the free base, followed byconcentration, unless specified otherwise.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 9 (Advanced ChemistryDevelopment, Toronto, Ontario, Canada).

Abbreviations and acronyms used herein include the following:

Term Acronym Acetonitrile ACN tert-Butylcarbamoyl Boc or BOC t-butanolt-buOH Dichloroethane DCE Dichloromethane DCM Diisopropylether DIPEDiisopropylethylamine DIPEA or Hunig's base N,N-Dimethylformamide DMFDimethylsulfoxide DMSO 1,1′-Bis(diphenylphosphino)ferrocene Dppf or dppfN-(3-Dimethylaminopropyl)-N′- ECD or EDCI ethylcarbodiimide EthylAcetate EtOAc, or EA Ethanol EtOH2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- HATU tetramethylaminiumhexafluorophosphate High-pressure liquid chromatography HPLC1-Hydroxybenzotriazole HOBt Isopropyl alcohol IPA or iPrOH Isopropylamine iPrNH₂ Methyl Iodide MeI Methanol-d₁ MeOD Methanol MeOH1,1′-Bis(diphenylphosphino)ferrocene- Pd(dppf)₂Cl₂palladium(II)dichloride Potassium Acetate KOAc Sodium Ethoxide NaOEtTriphenylphosphine Ph₃P Tetrakis(triphenylphosphine)palladium(0)(Ph₃P)₄Pd Supercritical fluid HPLC SFC Silica gel chromatography sgcTriethylamine TEA, Et₃N Tetrahydrofuran THF Tetrahydropyran THPTrifluoroacetic acid TFA Thin Layer Chromatography TLC Phenyl Ph

Intermediate 1: 4-Phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 1, Step a: ten-Butyl4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate(2.00 g, 7.39 mmol) in EtOH (37 mL) was added formamidine hydrochloride(910 mg, 11.08 mmol) followed by NaOEt (6.89 mL, 2.68 M in EtOH)dropwise. The mixture was then heated to reflux overnight. The mixturewas concentrated in vacuo and then dissolved in a minimum amount ofwater. The pH was adjusted to pH 7 with 1 N HCl. The aqueous layer wasthen saturated with solid NaCl and extracted with a combination of EtOAcand DCM. The combined organic extracts were dried over Na₂SO₄, filteredand concentrated in vacuo. Chromatography on SiO₂ eluting with IPA/EtOAcafforded the desired product as a white solid (993 mg, 53%). MS (ESI)mass calcd. C₁₂H₁₇N₃O₃, 251.13; m/z found 252.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.05 (s, 1H), 4.42 (s, 2H), 3.69-3.61 (m, 2H), 2.63 (s, 2H),1.49 (s, 9H).

Intermediate 1, Step b: ten-butyl4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of the product of Intermediate 1, step a (966 mg, 3.84mmol) in DCM (19 mL) was added Et₃N (0.64 mL, 4.61 mmol) followed bytriflic anhydride (0.72 mL, 4.23 mmol) dropwise at 0° C. The mixture wasquenched with the addition of saturated aqueous NH₄Cl solution. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. Chromatography on SiO₂ eluting with EtOAc/hexanesafforded the desired product as a viscous colorless oil (427 mg, 29%).MS (ESI) mass calcd. C₁₃H₁₆F₃N₃O₅S, 383.08; m/z found 328.0[M+H-^(t)Bu]⁺. ¹H NMR (500 MHz, CDCl₃): 8.83 (s, 1H), 4.71 (s, 2H), 3.75(t, J=5.7 Hz, 2H), 2.85 (t, J=5.5 Hz, 2H), 1.50 (s, 9H).

Intermediate 1, Step c: tert-butyl4-phenyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a 25 mL round bottom flask was added the following reagents:phenylboronic acid (210 mg, 1.67 mmol), PdCl₂dppf (33 mg, 0.04 mmol),dppf (13 mg, 0.02 mmol) and K₃PO₄ (366 mg, 1.67 mmol). The product ofIntermediate 1, step B (427 mg, 1.11 mmol) was dissolved in dioxane (11mL) and added. The mixture was heated to 100° C. overnight. The mixturewas concentrated in vacuo and then dissolved in toluene and filteredthrough Celite. The toluene was then concentrated in vacuo andchromatography on SiO₂ eluting EtOAc/hexane afforded the desired productas a viscous orange oil (272 mg, 78%). MS (ESI) mass calcd. C₁₈H₂₁N₃O₂,311.16; m/z found 312.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.08 (s, 1H),7.63-7.58 (m, 2H), 7.53-7.46 (m, 3H), 4.72 (s, 2H), 3.62 (t, J=5.6 Hz,2H), 2.91 (s, 2H), 1.51 (s, 9H).

Intermediate 1, step d:4-Phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Intermediate 1, step c (265 mg, 0.85 mmol) in DCM (4mL) was added TFA (0.85 mL). After stirring 3 h, the mixture wasconcentrated in vacuo. The residue was dissolved in DCM and treated withsaturated aqueous NaHCO₃ solution. The aqueous layer was then extractedwith DCM and EtOAc. The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. Chromatography on SiO₂ eluting with2 M NH₃ in MeOH/DCM afforded the desired product as a dark orange oil(172 mg, 96%). MS (ESI) mass calcd. C₁₃H₁₃N₃, 211.11; m/z found 212.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.03 (s, 1H), 7.62-7.56 (m, 2H),7.52-7.43 (m, 3H), 4.16 (s, 2H), 3.09 (t, J=5.7 Hz, 2H), 2.85 (t, J=5.6Hz, 2H).

Intermediate 2: tert-Butyl4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of the product of Intermediate 1, step a (1.26 g, 5.02mmol) in DCE (36 mL) was added PPh₃ (2.69 g, 10.05 mmol) followed byCCl₄ (1.46 mL, 15.07 mmol) and the mixture was heated to 70° C. for 2.5h. The mixture was concentrated in vacuo and chromatographed on SiO₂eluting with EtOAc/hexane to afford the desired compound as a paleyellow solid (1.20 g, 88%). MS (ESI) mass calcd. C₁₂H₁₆ClN₃O₂, 269.09;m/z found 270.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.79 (s, 1H), 4.65 (brs, 2H), 3.80-3.68 (m, 2H), 2.93-2.82 (m, 2H), 1.49 (s, 9H).

Intermediate 3:4-Chloro-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 3, step a:4-Chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To Intermediate 2 (521 mg, 1.93 mmol) in DCM (10 mL) was added TFA (4mL). After stirring 3 h, the mixture was concentrated in vacuo and theresidue was redissolved in DCM, cooled to 0° C. in an ice bath andtreated with saturated aqueous NaHCO₃ solution. After stirring for 30min, the layers were separated and the aqueous layer extracted with 5%IPA in DCM. The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to a very pale yellow solid (304, 93%). Thismaterial was used as is without further purification. MS (ESI) masscalcd. C₇H₈ClN₃, 169.04; m/z found 170.1 [M+H]⁺.

Intermediate 3, step b:4-Chloro-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of the product of Intermediate 3 step a (305 mg, 1.80mmol) in DCM (9 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid(404 mg, 1.80 mmol) followed by EDCI (517 mg, 2.70 mmol), HOBt (170 mg,1.26 mmol) and TEA (0.50 mL, 3.60 mmol). The mixture was stirredovernight and then loaded directly on a column. Chromatography on SiO₂eluting with EtOAc/hexane afforded the desired product (267 mg, 39%) and4-(1H-benzotriazol-1-yloxy)-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(203 mg, 24%) as a side product. MS (ESI) mass calcd. C₁₅H₁₀Cl₂F₃N₃O,375.02; m/z found 376.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.89-8.74 (m,1H), 7.84-7.76 (m, 1H), 7.55-7.45 (m, 2H), 5.13-4.94 (m, 1H), 4.54-4.35(m, 1H), 4.23-4.06 (m, 1H), 3.64-3.52 (m, 1H), 3.10-2.78 (m, 2H).

Intermediate 4:4-(1H-Benzotriazol-1-yloxy)-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 4 was formed as a side product during the synthesis ofIntermediate 3 in step b. MS (ESI) mass calcd. C₂₁H₁₄ClF₃N₆O₂, 474.08;m/z found 475.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.55-8.40 (m, 1H),8.16-8.11 (m, 1H), 7.86-7.78 (m, 1H), 7.60-7.42 (m, 5H), 5.18-5.03 (m,1H), 4.62-4.42 (m, 1H), 4.32-4.18 (m, 1H), 3.75-3.62 (m, 1H), 3.30-3.01(m, 2H).

Intermediate 5:4-Chloro-7-[(2,4-dichlorophenyl)carbonyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 5, step a:4-Chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To Intermediate 2 (1.23 g, 4.54 mmol) in DCM (23 mL) was added TFA (9mL). After stirring 3 h, the mixture was concentrated in vacuo and usedwithout further purification. MS (ESI) mass calcd. C₇H₈ClN₃, 169.04; m/zfound 170.1 [M+H]⁺.

Intermediate 5, step b:4-Chloro-7-[(2,4-dichlorophenyl)carbonyl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a heterogeneous mixture of 2,3-dichlorobenzoic acid (894 mg, 4.68mmol) in DCM (23 mL) was added 2 M oxalyl chloride in DCM (2.73 mL)followed by 3 drops of DMF. Gentle bubbling proceeded and after bubblingwas complete, the mixture was concentrated in vacuo and then rechargedwith fresh DCM (12 mL). Then the product of Intermediate 5, step a (771mg, 4.54 mmol) was added as a solution in DCM (12 mL) followed by Et₃N(2.97 mL, 21.36 mmol) at 0° C. The reaction was allowed to warm to roomtemperature over several hours and then was partially concentrated invacuo and filter loaded on SiO₂ eluting with EtOAc/hexane to afford thetitle compound (585 mg, 38%) MS (ESI) mass calcd. C₁₄H₁₀Cl₃N₃O, 340.99;m/z found 342.0 [M+H]⁺ and1-(4-chloro-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2,2,2-trifluoroethanoneas a side product (262 mg, 22%).

Intermediate 6:1-(4-Chloro-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2,2,2-trifluoroethanone

Intermediate 6 was formed as a side product during the synthesis ofIntermediate 4 in step b. MS (ESI) mass calcd. C₉H₇ClF₃N₃O, 265.02; m/zfound 266.0 [M+H]⁺.

Example 17-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of Intermediate 1 (55 mg, 0.26 mmol) in DCM (3 mL) wasadded 2-chloro-3-(trifluoromethyl)benzoic acid (60 mg, 0.26 mmol)followed by EDCI (75 mg, 0.39 mmol), HOBt (28 mg, 0.21 mmol) and TEA(0.72 mL, 0.52 mmol). The mixture was stirred overnight and then loadeddirectly on a column. Chromatography on SiO₂ eluting with EtOAc/hexaneafforded the desired product as a colorless foam (80 mg, 73%). MS (ESI)mass calcd. C₂₁H₁₅ClF₃N₃O, 417.09; m/z found 418.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 9.16-9.03 (m, 1H), 7.82-7.77 (m, 1H), 7.65-7.46 (m, 7H),5.16-5.02 (m, 1H), 4.61-4.42 (m, 1H), 4.09-3.97 (m, 1H), 3.52-3.38 (m,1H), 3.11-2.83 (m, 2H).

Example 27-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 1substituting 2,3-dichlorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) mass calcd.C₂₀H₁₅Cl₂N₃O, 383.06; m/z found 384.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):9.16-9.02 (m, 1H), 7.65-7.46 (m, 6H), 7.34-7.29 (m, 1H), 7.28-7.26 (m,1H), 5.07 (s, 1H), 4.61-4.43 (m, 1H), 4.03-3.98 (m, 1H), 3.52-3.38 (m,1H), 3.13-2.82 (m, 2H).

Example 34-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-3-methylbenzonitrile

The title compound was prepared in a manner analogous to Example 74substituting 4-cyano-2-methylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI) mass calcd. C₂₁H₂₀N₆O, 372.2; m/z found 373.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 11.65-10.82 (s, 1H), 7.83-7.29 (m,4H), 7.04-6.73 (m, 1H), 5.88-5.27 (m, 1H), 4.81-3.91 (m, 2H), 3.61-2.95(m, 2H), 2.90-2.06 (m, 6H), 1.42-1.08 (m, 3H).

Example 47-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Example 4, Step a: tert-butyl4-(1H-pyrazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a microwave vial was added Intermediate 2 (113 mg, 0.42 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (138 mg,0.71 mmol) followed by dioxane (4 mL) and 2M Na₂CO₃ (0.52 mL). To thismixture was added Pd(PPh₃)₄ (24 mg, 0.02 mmol) and the reaction heatedin the microwave for 1 h at 150° C. The reaction was diluted with waterand extracted with DCM and EtOAc. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo. Chromatography onSiO₂ eluting with EtOAc/hexane afforded the desired product as a slowlycrystallizing white solid (97 mg, 77%). MS (ESI) mass calcd. C₁₅H₁₉N₅O₂,301.15; m/z found 302.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.96 (s, 1H),8.21 (s, 2H), 4.68 (s, 2H), 3.82-3.70 (m, 2H), 3.07-2.93 (m, 2H), 1.51(s, 9H).

Example 4, step b:4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 4, step a (81 mg, 0.27 mmol) in DCM (3 mL) wasadded TFA (0.27 mL). After stirring 3 h the mixture was concentrated invacuo and loaded directly on a column. Chromatography on SiO₂ elutingwith 2 M NH₃ in MeOH/DCM afforded the desired product as a white solid(22 mg, 41%). MS (ESI) mass calcd. 201.10; m/z found 202.0 [M+H]⁺

Example 4, step c:7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 1substituting the product of Example 4, step b for Intermediate 1 and2,3-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.MS (ESI) mass calcd. C₁₇H₁₃C₁₂N₅O, 373.05; m/z found 373.9 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 9.04-8.88 (m, 1H), 8.27-8.13 (m, 2H), 7.59-7.51(m, 1H), 7.38-7.27 (m, 2H), 5.09-4.99 (m, 1H), 4.58-4.39 (m, 1H),4.19-4.09 (m, 1H), 3.66-3.52 (m, 1H), 3.21-2.89 (m, 2H).

Example 57-[(2,3-Dichlorophenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 4substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Example4, step a. MS (ESI) mass calcd. C₁₈H₁₅C₁₂N₅O, 387.07; m/z found 387.9[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.99-8.84 (m, 1H), 8.07-7.94 (m, 2H),7.58-7.50 (m, 1H), 7.36-7.27 (m, 1H), 7.24-7.21 (m, 1H), 5.06-4.96 (m,1H), 4.54-4.37 (m, 1H), 4.16-4.09 (m, 1H), 4.02-3.96 (m, 3H), 3.64-3.51(m, 1H), 3.16-2.86 (m, 2H).

Example 67-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 4substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Example4, step a and 2-chloro-3-methylbenzoic acid for 2,3-dichlorobenzoic acidin Example 4, step c. MS (ESI) mass calcd. C₁₉H₁₈ClN₅O, 367.12; m/zfound 367.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.00-8.84 (m, 1H),8.09-7.93 (m, 2H), 7.35-7.27 (m, 1H), 7.25-7.13 (m, 2H), 5.10-4.95 (m,1H), 4.58-4.38 (m, 1H), 4.19-4.07 (m, 1H), 4.04-3.96 (m, 3H), 3.65-3.53(m, 1H), 3.18-2.85 (m, 2H), 2.48-2.37 (m, 3H).

Example 77-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Method I Example 7, Step I-a: tert-Butyl4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

The title compound was prepared in a manner analogous to Example 4, stepa, substituting 1-(tetrahydropyran-2-yl)-1H-pyrazole-5-boronic acidpinacol ester for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI)mass calcd. C₂₀H₂₇N₅O₃, 385.21; m/z found 386.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 9.10 (s, 1H), 7.66 (d, J=1.8 Hz, 1H), 6.52 (d, J=1.8 Hz, 1H),5.88-5.79 (m, 1H), 5.30 (s, 1H), 4.93-4.81 (m, 1H), 4.61-4.53 (m, 1H),4.04-3.86 (m, 2H), 3.48-3.29 (m, 2H), 2.96-2.77 (m, 2H), 2.53-2.42 (m,1H), 2.14-2.06 (m, 2H), 1.73-1.61 (m, 2H), 1.51 (s, 9H).

Example 7, step I-b:4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 7, step I-a (191 mg, 0.50 mmol) in DCM (2 mL)was added 4 M HCl in dioxane (1.24 mL). After 2 h the reaction wascomplete and concentrated in vacuo to a red solid. This material wasused without further purification. MS (ESI) mass calcd. C₁₀H₁₁N₅,201.10; m/z found 202.1 [M+H]⁺.

Example 7, step I-c:7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of the product of Example 7, step I-b (41 mg, 0.17 mmol)in DCM (2 mL) was added 2,3-dichlorobenzoic acid (33 mg, 0.17 mmol)followed by EDCI (33 mg, 0.17 mmol), HOBt (16 mg, 0.12 mmol) and TEA(0.60 mL, 0.44 mmol). The mixture was stirred overnight and then loadeddirectly on a Prep Agilent system with a XBridge C18 OBD 50×100 mmcolumn eluting with 5 to 99% 0.05% NH₄OH in H₂O/ACN over 17 min toafford the desired product as a colorless solid (8 mg, 12%). MS (ESI)mass calcd. C₁₇H₁₃Cl₂N₅O, 373.05; m/z found 374.1 [M+H]⁺. ¹H NMR (600MHz, CDCl₃): 11.19 (br s, 1H), 9.10-8.93 (m, 1H), 7.75-7.68 (m, 1H),7.58-7.51 (m, 1H), 7.36-7.22 (m, 2H), 7.00-6.93 (m, 1H), 5.16-4.99 (m,1H), 4.60-4.42 (m, 1H), 4.18-4.11 (m, 1H), 3.64-3.50 (m, 1H), 3.39-3.09(m, 2H).

Method II Example 7, Step II-a:7-[(2,3-dichlorophenyl)carbonyl]-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 4, stepa, substituting Intermediate 5 for Intermediate 2 and1-(tetrahydropyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI)mass calcd. C₂₂H₂₁Cl₂N₅O₂, 457.11; m/z found 458.1 [M+H]⁺.

Example 7, step II-b:7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of the product of, Example 7, step I-a (749 mg, 1.63 mmol)in MeOH (8 mL) was added 6 M HCl (1.09 mL). The mixture was aged for 3 hand then neutralized with solid NaOH (74 mg, 1.84 mmol) dissolved in aminimum amount of water. The mixture was then concentrated in vacuo. Thematerial was dissolved in DCM and stirred overnight. Filtration removedthe inorganic solids and the filtrate was concentrated in vacuo.Chromatography on a Prep Agilent system with a XBridge C18 OBD 50×100 mmcolumn eluting with 5 to 99% 0.05% NH₄OH in H₂O/ACN over 17 min affordedthe desired product as a colorless solid (301 mg, 49%). MS (ESI) masscalcd. C₁₇H₁₃Cl₂N₅O, 373.05; m/z found 374.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 9.10-8.93 (m, 1H), 7.76-7.67 (m, 1H), 7.58-7.51 (m, 1H),7.36-7.21 (m, 2H), 7.07-6.83 (m, 1H), 5.15-4.98 (m, 1H), 4.61-4.42 (m,1H), 4.19-4.12 (m, 1H), 3.65-3.52 (m, 1H), 3.44-3.06 (m, 2H).

Example 87-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example7-Method I substituting 2-chloro-3-methylbenzoic acid for2,3-dichlorobenzoic acid in Example 7, step I-c. MS (ESI) mass calcd.C₁₈H₁₆ClN₅O, 353.10; m/z found 354.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):9.11-8.92 (m, 1H), 7.78-7.66 (m, 1H), 7.35-7.13 (m, 3H), 6.99-6.89 (m,1H), 5.17-4.98 (m, 1H), 4.62-4.42 (m, 1H), 4.21-4.08 (m, 1H), 3.66-3.50(m, 1H), 3.42-3.05 (m, 2H), 2.47-2.38 (m, 3H).

Example 97-[(2,3-Dimethylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example7-Method I substituting 2,3-dimethylbenzoic acid for 2,3-dichlorobenzoicacid in Example 7, step I-c. MS (ESI) mass calcd. C₁₉H₁₉N₅O, 333.16; m/zfound 334.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.10-8.90 (m, 1H),7.74-7.65 (m, 1H), 7.25-6.90 (m, 4H), 5.28-4.88 (m, 1H), 4.55-4.44 (m,1H), 4.31-4.01 (m, 1H), 3.67-3.49 (m, 1H), 3.35 (s, 1H), 3.14-3.04 (m,1H), 2.35-2.11 (m, 6H).

Example 107-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example7-Method I substituting 2-methyl-3-(trifluoromethyl)benzoic acid for2,3-dichlorobenzoic acid in Example 7, step I-c. MS (ESI) mass calcd.C₁₉H₁₆F₃N₅O, 387.13; m/z found 388.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃):9.10-8.93 (m, 1H), 7.75-7.67 (m, 2H), 7.45-7.34 (m, 2H), 7.01-6.93 (m,1H), 5.28-4.88 (m, 1H), 4.52-4.39 (m, 1H), 4.27-4.05 (m, 1H), 3.63-3.47(m, 1H), 3.41-3.28 (m, 1H), 3.17-3.11 (m, 1H), 2.49-2.35 (m, 3H).

Example 117-[(2,3-Dichlorophenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Example 11, Step a: tert-Butyl4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.To a microwave vial was added Intermediate 2 (136 mg, 0.50 mmol) andPd(Ph₃)₄ (29 mg, 0.03 mmol). To these solid reagents were quickly addeddegassed dioxane (3 mL) and 2-tri-n-butylstannylpyridine (327 mg, 0.75mmol). The microwave tube was sealed and the reaction heated at 140° C.for 90 min. The mixture was diluted with saturated aqueous KF andstirred for 30 min. EtOAc was added and the layers separated. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Chromatography on SiO₂ eluting with EtOAc/hexaneafforded the desired product (157 mg, 99%). MS (ESI) mass calcd.C₁₇H₂₀N₄O₂, 312.16; m/z found 313.2 [M+H]⁺.

Example 11, Step b:4-Pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 11, step a (157 mg, 0.50 mmol) in DCM (3 mL)was added TFA (1.00 mL). After stirring for 3 h, the mixture wasconcentrated in vacuo and loaded directly on a Prep Agilent system witha XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH₄OH inH₂O/ACN over 17 min to afford the desired product as a tan solid (89 mg,83%). MS (ESI) mass calcd. C₁₂H₁₂N₄, 212.11; m/z found 213.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 9.05 (s, 1H), 8.71 (s, 1H), 8.06-7.94 (m, 1H),7.93-7.81 (m, 1H), 7.45-7.32 (m, 1H), 4.17 (s, 2H), 3.16 (s, 4H).

Example 11, step c:7-[(2,3-Dichlorophenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 7, stepI-c (26 mg, 48%). MS (ESI) mass calcd. C₁₉H₁₄Cl₂N₄O, 384.05; m/z found385.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.19-9.01 (m, 1H), 8.77-8.62 (m,1H), 8.17-8.06 (m, 1H), 7.93-7.84 (m, 1H), 7.57-7.50 (m, 1H), 7.44-7.36(m, 1H), 7.34-7.22 (m, 2H), 5.23-4.95 (m, 1H), 4.63-4.44 (m, 1H),4.15-3.94 (m, 1H), 3.53-3.27 (m, 3H).

Example 127-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 11substituting 2-chloro-3-(trifluoromethyl)benzoic acid for2,3-dichlorobenzoic acid in Example 11, step c. MS (ESI) mass calcd.C₂₀H₁₄ClF₃N₄O, 418.08; m/z found 419.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):9.18-9.02 (m, 1H), 8.76-8.63 (m, 1H), 8.17-8.08 (m, 1H), 7.92-7.86 (m,1H), 7.81-7.77 (m, 1H), 7.58-7.36 (m, 3H), 5.26-4.94 (m, 1H), 4.63-4.44(m, 1H), 4.21-3.91 (m, 1H), 3.53-3.27 (m, 3H).

Example 137-[(2-Chloro-3-methylphenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 11substituting 2-chloro-3-methylbenzoic acid for 2,3-dichlorobenzoic acidin Example 11, step c. MS (ESI) mass calcd. C₂₀H₁₇ClN₄O, 364.11; m/zfound 365.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.16-9.02 (m, 1H),8.75-8.64 (m, 1H), 8.13-8.06 (m, 1H), 7.91-7.85 (m, 1H), 7.43-7.35 (m,1H), 7.32-7.14 (m, 3H), 5.24-4.95 (m, 1H), 4.64-4.46 (m, 1H), 4.13-3.96(m, 1H), 3.52-3.35 (m, 2H), 3.30-3.25 (m, 1H), 2.46-2.39 (m, 3H).

Example 147-[(2,3-Dichlorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 11substituting 2-tributylstannylpyrazine for 2-tri-n-butylstannylpyridinein Example 11, step a. MS (ESI) mass calcd. C₁₈H₁₃Cl₂N₅O, 385.05; m/zfound 386.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.48-9.42 (m, 1H),9.21-9.06 (m, 1H), 8.71-8.60 (m, 2H), 7.56-7.52 (m, 1H), 7.35-7.22 (m,2H), 5.19-5.01 (m, 1H), 4.64-4.46 (m, 1H), 4.09-4.04 (m, 1H), 3.57-3.43(m, 2H), 3.37-3.23 (m, 1H).

Example 157-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 11substituting 2-tributylstannylpyrazine for 2-tri-n-butylstannylpyridinein Example 11, step a and 2-methyl-3-(trifluoromethyl)benzoic acid for2,3-dichlorobenzoic acid in Example 11, step c. MS (ESI) mass calcd.C₂₀H₁₆F₃N₅O, 399.13; m/z found 400.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃):9.48-9.43 (m, 1H), 9.21-9.06 (m, 1H), 8.72-8.59 (m, 2H), 7.73-7.68 (m,1H), 7.45-7.35 (m, 2H), 5.29-4.96 (m, 1H), 4.55-4.45 (m, 1H), 4.18-3.99(m, 1H), 3.55-3.42 (m, 2H), 3.32-3.17 (m, 1H), 2.49-2.38 (m, 3H).

Example 167-[(2-Chloro-4,5-difluorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 11substituting 2-tributylstannylpyrazine for 2-tri-n-butylstannylpyridinein Example 11, step a and 2-chloro-4,5-difluorobenzoic acid for2,3-dichlorobenzoic acid in Example 11, step c. MS (ESI) mass calcd.C₁₈H₁₂ClF₂N₅O, 387.07; m/z found 388.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):9.49-9.42 (m, 1H), 9.22-9.07 (m, 1H), 8.72-8.59 (m, 2H), 7.34-7.27 (m,1H), 7.25-7.19 (m, 1H), 5.22-4.94 (m, 1H), 4.67-4.46 (m, 1H), 4.08-4.01(m, 1H), 3.57-3.51 (m, 1H), 3.47-3.42 (m, 1H), 3.39-3.24 (m, 1H).

Example 177-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 4, stepa, substituting Intermediate 3 for Intermediate 2 and1-(tetrahydropyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI)mass calcd. C₂₃H₂₁ClF₃N₅O₂, 491.13; m/z found 492.1 [M+H]⁺ 1H NMR (500MHz, CDCl₃): 9.19-9.03 (m, 1H), 7.82-7.77 (m, 1H), 7.71-7.61 (m, 1H),7.57-7.46 (m, 2H), 6.59-6.45 (m, 1H), 5.92-5.79 (m, 1H), 5.37-4.82 (m,1H), 4.65-4.42 (m, 2H), 3.92-3.83 (m, 1H), 3.68-3.32 (m, 2H), 3.14-2.75(m, 2H), 2.53-2.40 (m, 1H), 2.16-2.05 (m, 2H), 1.73-1.58 (m, 2H),1.54-1.49 (m, 1H).

Example 18(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

To a solution of Example 17 (224 mg, 0.46 mmol) in MeOH (2 mL) was added6 M HCl (0.30 mL). The mixture was aged for 3 h and then neutralizedwith solid NaOH (74 mg, 1.84 mmol) dissolved in a minimum amount ofwater. The mixture was then concentrated in vacuo. The material wasdissolved in DCM and stirred overnight. Filtration removed the inorganicsolids and the filtrate was concentrated in vacuo. Chromatography onSiO₂ EtOAc/hexane afforded the desired compound as a colorless foam (151mg, 81%). MS (ESI) mass calcd. C₁₈H₁₃ClF₃N₅O, 407.08; m/z found 408.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.10-8.95 (m, 1H), 7.83-7.77 (m, 1H),7.76-7.69 (m, 1H), 7.58-7.45 (m, 2H), 7.05-6.89 (m, 1H), 5.18-4.98 (m,1H), 4.60-4.41 (m, 1H), 4.25-4.04 (m, 1H), 3.64-3.51 (m, 1H), 3.43-3.09(m, 2H).

Example 197-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of Example 18 (137 mg, 0.33 mmol) in DMF (3 mL) was addedNaH, 60% dispersion in mineral oil (16 mg, 0.40 mmol). After 30 minutesMeI (0.03 mL, 0.40 mmol) was then added. After several hours thereaction was diluted with water and then extracted with EtOAc. Thecombined organic layers were washed with water, dried over Na₂SO₄,filtered and concentrated in vacuo. Purification on a Prep Agilentsystem with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99%0.05% NH₄OH in H₂O/ACN over 17 min to afforded the title compound as awhite solid (61.2 mg, 43%). MS (ESI) mass calcd. C₁₉H₁₅ClF₃N₅O, 421.09;m/z found 422.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.09-8.92 (m, 1H),7.82-7.75 (m, 1H), 7.58-7.42 (m, 3H), 7.06-7.01 (m, 1H), 5.19-4.92 (m,1H), 4.58-4.38 (m, 1H), 4.22-3.94 (m, 4H), 3.57-3.22 (m, 3H).

Example 207-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Example 20, Step a:4-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 4, stepa, substituting Intermediate 6 for Intermediate 2 and1-(tetrahydropyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI)mass calcd. C₁₅H₁₉N₅O, 285.156; m/z found 286.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 9.09-9.03 (m, 1H), 7.70-7.63 (m, 1H), 6.56-6.50 (m, 1H),5.84-5.75 (m, 1H), 4.27-4.00 (m, 2H), 3.96-3.88 (m, 1H), 3.50-3.39 (m,1H), 3.32-3.25 (m, 1H), 3.12-3.03 (m, 1H), 2.99-2.90 (m, 1H), 2.86-2.77(m, 1H), 2.53-2.42 (m, 1H), 2.15-2.03 (m, 2H), 1.74-1.48 (m, 3H).

Example 20, Step b:7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 1substituting the product of Example 20, step a for Intermediate 1 and2,4-dichloro-3-fluorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) mass calcd.C₂₂H₂₀Cl₂FN₅O₂, 475.10; m/z found 476.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):9.18-9.03 (m, 1H), 7.70-7.62 (m, 1H), 7.47-7.39 (m, 1H), 7.14-7.07 (m,1H), 6.58-6.45 (m, 1H), 5.92-5.80 (m, 1H), 5.36-4.78 (m, 1H), 4.64-4.39(m, 1H), 3.94-3.31 (m, 4H), 3.17-2.75 (m, 2H), 2.53-2.39 (m, 1H),2.18-2.06 (m, 2H), 1.73-1.60 (m, 2H), 1.55-1.48 (m, 1H).

Example 20, Step c:7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

TFA (0.97 mL, 0.24 mmol) was added to a solution of the product ofExample 20, step b (116 mg, 0.24 mmol) in DCM (1 mL) containingtriethylsilane (0.1 mL, 0.61 mmol). The reaction was stirred for 30 min.The reaction was concentrated in vacuo and then azeotroped 2x withtoluene. The residue was purified on SiO₂ eluting with EtOAc/hexane toafford the title compound as a white solid (97 mg, 100%). MS (ESI) masscalcd. C₁₇H₁₂Cl₂FN₅O, 391.04; m/z found 392.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 9.11-8.93 (m, 1H), 7.77-7.67 (m, 1H), 7.48-7.37 (m, 1H),7.15-7.07 (m, 1H), 6.99-6.90 (m, 1H), 5.14-4.96 (m, 1H), 4.61-4.40 (m,1H), 4.17-4.11 (m, 1H), 3.67-3.51 (m, 1H), 3.36-3.08 (m, 2H).

Example 217-[(2-chloro-4-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 20substituting 2-chloro-4-fluorobenzoic acid for2,4-dichloro-3-fluorobenzoic acid in Example 20, step b. MS (ESI) masscalcd. C₁₇H₁₃ClFN₅O, 357.08; m/z found 358.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 9.10-8.92 (m, 1H), 7.78-7.66 (m, 1H), 7.39-7.31 (m, 1H),7.25-7.04 (m, 2H), 6.98-6.89 (m, 1H), 5.16-4.93 (m, 1H), 4.64-4.40 (m,1H), 4.18-4.08 (m, 1H), 3.67-3.52 (m, 1H), 3.35-3.05 (m, 2H).

Example 227-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Example 22, Step a: To a suspension of NaH (60% dispersion in mineraloil (25 mg, 0.62 mmol)) in DMF (3 mL) was added pyrazole (39 mg, 0.57mmol). When gas evolution had ceased and the mixture was homogeneous,Intermediate 2 was added (139 mg, 0.51 mmol). The reaction immediatelyturned a dark red color and was warm to the touch. After agingovernight, the mixture was diluted with H₂O and extracted with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Chromatography on SiO₂ eluting with EtOAc/hexaneafforded the desired compound as a viscous colorless oil (81 mg, 52%).MS (ESI) mass calcd. C₁₅H₁₉N₅O₂, 301.15; m/z found 302.0 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 8.83 (s, 1H), 8.63-8.56 (m, 1H), 7.82-7.77 (m, 1H),6.51-6.47 (m, 1H), 4.77-4.65 (m, 2H), 3.72-3.64 (m, J=5.8 Hz, 2H),3.42-3.32 (m, 2H), 1.50 (s, 9H).

Example 22, Step b:4-(1H-Pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 22, step a (78 mg, 0.26 mmol) in DCM (1 mL)was added TFA (0.26 mL). After stirring 3 h the reaction wasconcentrated in vacuo. The residue was redissolved in DCM and treatedwith Dowex 550A resin to neutralize the TFA salt. The resin was removedby filtration and concentration afforded a yellow solid (50 mg, 97%).This material was used without subsequent purification. MS (ESI) masscalcd. C₁₀H₁₁N₅, 201.10; m/z found 202.0 [M+H]⁺.

Example 22, step c:7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 1substituting the product of Example 22, step b for Intermediate 1 and2,3-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.MS (ESI) mass calcd. C₁₇H₁₃Cl₂N₅O, 373.05; m/z found 374.1 [M+H]⁺. ¹HNMR (600 MHz, CDCl₃): 8.91-8.76 (m, 1H), 8.66-8.61 (m, 1H), 7.85-7.74(m, 1H), 7.57-7.51 (m, 1H), 7.35-7.22 (m, 2H), 6.53-6.48 (m, 1H),5.21-4.94 (m, 1H), 4.60-4.42 (m, 1H), 4.14-4.01 (m, 1H), 3.58-3.49 (m,2H), 3.47-3.32 (m, 1H).

Example 237-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 22substituting 1H-1,2,3-triazole for pyrazole in Example 22, step a. MS(ESI) mass calcd. C₁₆H₁₂Cl₂N₆O, 374.05; m/z found 375.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 9.12-8.97 (m, 1H), 8.02-7.95 (m, 2H), 7.58-7.52 (m,1H), 7.36-7.23 (m, 2H), 5.23-5.04 (m, 1H), 4.67-4.49 (m, 1H), 4.13-4.08(m, 1H), 3.60-3.42 (m, 2H), 3.36-3.21 (m, 1H).

Example 247-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 22substituting 1H-1,2,3-triazole for pyrazole in Example 22, step a and2-chloro-3-(trifluoromethyl)benzoic acid for 2,4-dichlorobenzoic acid.MS (ESI) mass calcd. C₁₇H₁₂ClF₃N₆O, 408.07; m/z found 409.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 9.12-8.98 (m, 1H), 8.02-7.96 (m, 2H), 7.83-7.78(m, 1H), 7.58-7.47 (m, 2H), 5.27-5.03 (m, 1H), 4.66-4.48 (m, 1H),4.20-4.05 (m, 1H), 3.57-3.43 (m, 2H), 3.36-3.22 (m, 1H).

Intermediate 7: tert-butyl2-(dimethylamino)-4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

K₂CO₃ (563 mg, 4.07 mmol) and 1,1-dimethylguanidine sulfate (566 mg,2.04 mmol) were added to a suspension of ethylN—BOC-3-oxopiperidine-4-carboxylate in MeOH (2 mL) and H₂O (1 mL) in a40 mL vial. The reaction was heated in an aluminium block at 70° C. for90 minutes. LCMS analysis showed that the reaction was complete. Themixture was acidified to pH 3 and extracted with DCM (3x). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated toobtain tert-butyl2-(dimethylamino)-4-hydroxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylateas a pale yellow solid which was used without further purification. MS(ESI): mass calcd. for C₁₄H₂₂N₄O₃, 294.3; m/z found, 295.3 [M+H]⁺. ¹HNMR (400 MHz, MeOD) δ 4.29-4.11 (m, 2H), 3.71-3.46 (m, 2H), 3.09 (s,6H), 2.42 (t, J=5.8 Hz, 2H), 1.58-1.38 (m, 9H).

Intermediate 8: tert-butyl4-chloro-2-(dimethylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Triphenylphosphine (186 mg, 0.694 mmol) was added to a solution oftert-butyl4-hydroxy-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(92 mg, 0.347 mmol) and CCl₄ (160 mg, 1.04 mmol) in DCE (5 mL). Thereaction was heated at 70° C. for 2 hours, wherein TLC showed noremaining starting material. The mixture was concentrated mixture undervacuum and purified by sgc, 0-100% hexanes-EtOAc gradient over 12minutes. Tert-butyl4-chloro-2-(dimethylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylatewas isolated as a colorless oil (82 mg, 79%). MS (ESI): mass calcd. forC₁₄H₂₁ClN₄O₂, 312.8 m/z found, 313.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ4.37 (s, 2H), 3.73-3.46 (m, 2H), 2.66-2.52 (m, 2H), 1.53-1.34 (m, 9H).

Intermediate 9:N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

tert-Butyl tert-butyl4-chloro-2-(dimethylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(82 mg, 0.262 mmol), phenylboronic acid (49 mg, 0.393 mmol), Pd(Ph₃P)₄(15 mg, 0.013 mmol), and 1M aqueous Na₂CO₃ (0.524 mL, 0.524 mmol) werecombined in dioxane (4 mL) in a 40 mL vial and heated at 100° C.overnight in an aluminum heating block. The crude mixture waspartitioned between EtOAc/H₂O and extracted aqueous with EtOAc (2×). Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated. The product was purified by sgc 0-100% Hexane-EtOAcgradient over 8 minutes. The purified product was then dissolved in DCM(2 mL) and treated with TFA (0.5 mL), and stirred at room temp for 1hour. The mixture was neutralized with sat. NaHCO₃ solution andextracted with DCM (3x). The combined organic extracts were dried overMgSO₄, filtered and concentrated to isolateN,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine(85 mg, 99%). MS (ESI): mass calcd. for C₁₅H₁₈N₄, 254.3 m/z found, 255.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.54 (m, 2H), 7.48-7.41 (m, 3H),4.28-4.12 (m, 2H), 3.33-3.24 (m, 2H), 3.19 (s, 6H), 3.08-2.83 (m, 2H).

Example 257-[(2,3-Dichlorophenyl)carbonyl]-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

Intermediate 9 (40 mg, 0.157 mmol), HATU (60 mg, 0.157 mmol), TEA (32μL, 0.236 mmol) and 2,3-dichlorobenzoic acid (30 mg, 0.157 mmol) werecombined and stirred at room temperature for 2 h. The crude mixture wasconcentrated in vacuo and purified directly using reverse phase prepHPLC on an Agilent system with a XBridge C18 OBD 50×100 mm columneluting with 5 to 99% 0.05% NH₄OH in H₂O/ACN over 17 min to afford thedesired product as a yellow solid (30 mg, 45%). MS (ESI): mass calcd.for C₂₂H₂₀Cl₂N₄O, 426.1; m/z found, 427.3 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.64-7.59 (m, 1H), 7.59-7.55 (m, 1H), 7.54-7.49 (m, 1H),7.49-7.40 (m, 3H), 7.32-7.27 (m, 1H), 7.27-7.24 (m, 1H), 4.85 4.93-4.77(m, 1H), 4.47-4.16 (m, 1H), 4.03-3.79 (m, 1H), 3.45-3.27 (m, 1H),3.27-3.10 (m, 6H), 2.86 (t, J=5.7 Hz, 1H), 2.81-2.62 (m, 1H).

Example 267-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 25substituting 2-chloro-3-(trifluoromethyl)benzoic acid for2,3-dichlorobenzoic acid. MS (ESI): mass calcd. for C₂₃H₂₀ClF₃N₄O,460.9; m/z found, 461.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.81-7.73 (m,1H), 7.64-7.59 (m, 1H), 7.59-7.55 (m, 1H), 7.55-7.51 (m, 1H), 7.51-7.39(m, 4H), 4.99-4.77 (m, 1H), 4.42-4.19 (m, 1H), 4.05-3.82 (m, 1H),3.44-3.28 (m, 1H), 3.28-3.18 (s, 3H), 3.19-3.11 (s, 3H), 2.92-2.83 (t,J=5.8 Hz, 1H), 2.80-2.61 (m, 1H).

Intermediate 10: tert-butyl4-hydroxy-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

K₂CO₃ (535 mg, 3.87 mmol) and acetamidine hydrochloride (185 mg, 1.93mmol) were added to a suspension of ethylN—BOC-3-oxopiperidine-4-carboxylate (525 mg, 1.93 mmol) in MeOH (3 mL)and H₂O (1 mL) in a 40 mL vial. The reaction was heated in an aluminumblock at 70° C. for 90 minutes. LCMS analysis indicated completeconsumption of the starting material. The reaction mixture was thenacidified to pH 3 and extracted with DCM (3x). The combined organicextracts were dried over MgSO₄, filtered and concentrated to obtaintert-butyl4-hydroxy-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylateas a yellow oil. The product was used without further purification (473mg, 93%). MS (ESI): mass calcd. for C₁₃H₁₉N₃O₃ 265.1 m/z found,266.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 4.37 (s, 2H), 3.71-3.50 (m, 2H),2.60 (s, 2H), 2.50-2.38 (m, 3H), 1.52-1.41 (m, 9H).

Intermediate 11: tert-butyl4-chloro-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Triphenylphosphine (186 mg, 0.694 mmol) was added to a solutionIntermediate 10 (92 mg, 0.347 mmol) and CCl₄ (160 mg, 1.04 mmol) in DCE(5 mL). The reaction was heated at 70° C. for 2 hours after which, TLCindicated complete consumption of the starting material. The mixture wasconcentrated under vacuum and purified by sgc, with a 0-100%hexanes-EtOAc gradient over 12 minutes to provide tert-butyl4-chloro-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylatewas isolated as a pale yellow oil (73 mg, 74%). MS (ESI): mass calcd.for C₁₃H₁₈ClN₃O₂ 283.11 m/z found, 284.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃)δ 4.59 (s, 2H), 3.72 (t, J=5.9 Hz, 2H), 2.82 (t, J=5.9 Hz, 2H), 2.67 (s,3H), 1.49 (s, 9H).

Intermediate 12:2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 11 (73 mg, 0.293 mmol), phenylboronic acid (55 mg, 0.439mmol), Pd(Ph₃P)₄ (16 mg, 0.015 mmol), and 1M aqueous Na₂CO₃ (0.586 mL,0.586 mmol) were combined in dioxane (3 mL) in a microwave vial andheated at 150° C. for 1 h in the microwave. LCMS indicated completeconsumption of the starting material. The crude mixture was partitionedbetween EtOAc/H₂O and the aqueous extracted with EtOAc (2×). Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated. The product was purified by sgc 0-100% hexane-EtOAcgradient over 8 minutes. The purified product was then dissolved in DCM(2 mL) and treated with TFA (0.5 mL), and stirred at room temp for 1hour. The mixture was neutralized with sat. NaHCO₃ solution andextracted with DCM (3x). The combined organic extracts were dried overMgSO₄ filtered and concentrated to isolate2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine as a yellowoil (59 mg, 89%). MS (ESI): mass calcd. for C₁₄H₁₅N₃ 225.3 m/z found,226.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl3) δ 8.08-7.99 (m, 1H), 7.56-7.48 (m,1H), 7.49-7.34 (m, 3H), 4.23-4.13 (m, 1H), 3.84-3.66 (m, 1H), 3.48 (s,3H), 3.16 (t, J=5.7 Hz, 1H), 2.83 (t, J=5.6 Hz, 1H), 2.71 (s, 2H).

Example 277-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 12 for Intermediate 9. MS (ESI): mass calcd.for C₂₁H₁₇Cl₂N₃O, 397.1; m/z found, 398.3 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.63-7.57 (m, 1H), 7.56-7.43 (m, 5H), 7.35-7.28 (m, 1H),7.28-7.22 (m, 1H), 5.02 (s, 1H), 4.63-4.36 (m, 1H), 4.09-3.87 (m, 1H),3.50-3.33 (m, 1H), 3.05-2.86 (m, 2H), 2.81-2.61 (m, 3H).

Intermediate 13:4-(4-fluorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 9substituting Intermediate 11 for Intermediate 8 and4-fluorophenylboronic acid for phenylboronic acid. ¹H NMR (500 MHz,CDCl₃) δ 7.59-7.51 (m, 2H), 7.19-7.11 (m, 2H), 4.19-4.09 (s, 2H),3.19-3.07 (t, J=5.8 Hz, 2H), 2.87-2.76 (t, J=5.7 Hz, 2H), 2.74-2.67 (s,3H).

Example 287-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 13 for Intermediate 9. MS (ESI): mass calcd.for C₂₁H₁₆Cl₂FN₃O 415.1; m/z found, 416.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.66-7.49 (m, 3H), 7.36-7.12 (m, 4H), 5.07-4.96 (m, 1H),4.60-4.35 (m, 1H), 4.03-3.91 (m, 1H), 3.55-3.32 (m, 1H), 3.06-2.85 (m,2H), 2.78-2.64 (m, 3H).

Intermediate 14:2-amino-7-benzyl-5,6,7,8-tetrahdrorido[3,4-d]pyrimidin-4-ol

Guanidine carbonate (343 mg, 1.87 mmol) was added to a solution of1-benzyl-4-ethoxycarbonyl-3-piperidone hydrochloride (488 mg, 1.87 mmol)in tBuOH (18 mL). The reaction was heated to reflux for 2 hours and thenwas acidified with 1N HCl to pH 5 and stirred for 30 minutes. Themixture was filtered and the solids were dried to obtain2-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as ayellow solid (320 mg, 67%). MS (ESI): mass calcd. for C₁₄H₁₆N₄O 256.3m/z found, 257.2[M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 7.40-7.26 (m, 5H), 3.71(s, 2H), 3.25 (s, 2H), 2.73 (t, J=5.9 Hz, 2H), 2.46 (t, J=5.9 Hz, 2H).

Intermediate 15:7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

POCl₃ (0.580 mL, 6.24 mmol) was added to a suspension of Intermediate 14(160 mg, 0.624 mmol) and dimethyl aniline (79 μL, 0.624 mmol) in DCE (5mL). The reaction was heated to reflux overnight. The reaction was thenpoured over ice and neutralized with solid Na₂CO₃ and extracted withEtOAc (3x). The combined organic extracts were dried over MgSO₄,filtered and concentrated. The crude material was purified by sgc usinga 0-100% hexane-EtOAc gradient over 8 minutes.7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine wasisolated as a pale yellow oil. (22 mg, 12%). MS (ESI): mass calcd. forC₁₄H₁₅ClN₄ 274.7 m/z found, 275.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.39-7.26 (m, 5H), 4.92 (s, 2H), 3.76-3.60 (m, 2H), 3.44 (d, J=20.4 Hz,2H), 2.82-2.61 (m, 4H).

Intermediate 16:7-benzyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Intermediate 12substituting Intermediate 15 for Intermediate 11. MS (ESI): mass calcd.for C₂₀H₂₀N₄, 316.4; m/z found, 317.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.72-7.62 (m, 3H), 7.49-7.39 (m, 4H), 7.39-7.24 (m, 3H), 5.00 (s, 2H),3.69 (s, 2H), 3.57 (s, 2H), 2.78-2.58 (m, 4H).

Intermediate 17:4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

Intermediate 16 (24 mg, 0.0759 mmol), 1-chloroethyl chloroformate (17μL, 0.152 mmol), and DIEA, (26 μL, 0.152 mmol) were combined in DCM (3mL) and stirred overnight at room temperature. The reaction was quenchedwith MeOH (5 mL) and concentrated in vacuo. The resulting residue wasdissolved in MeOH (5 mL) and heated at 50° C. for 1 hr. The solution wasconcentrated in vacuo and the desired product was used without furtherpurification. MS (ESI): mass calcd. for C₁₃H₁₄N₄, 226.3; m/z found,227.2 [M+H]⁺.

Example 297-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 17 for Intermediate 9. MS (ESI): mass calcd.for C₂₀H₁₆Cl₂N₄O, 398.1; m/z found, 399.3 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.57-7.42 (m, 5H), 7.33-7.27 (m, 1H), 7.26-7.22 (m, 2H),5.10-4.77 (m, 3H), 4.44-4.20 (m, 1H), 4.07-3.84 (m, 1H), 3.48-3.29 (m,1H).

Intermediate 18:2-methyl-4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 11 (227 mg, 0.800 mmol), 2-tri-n-butylstannylpyridine (519mg, 1.20 mmol) and Pd(Ph₃P)₄ (46 mg, 0.04 mmol) were combined in amicrowave vial. Dioxane (2 mL) that had been degassed with a stream ofN₂ (g) was added and the vial was sealed and heated in a microwavereactor at 140° C. for 90 min. The reaction mixture was partitionedbetween EtOAc and H₂O and 2 g of 50% wt KF on celite was added. Theresulting mixture was stirred for 30 min and then filtered. The aqueousmaterial was extracted with EtOAc (2×) and the combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo.Chromatography on silica gel eluted with hexanes/EtOAc afforded thedesired product as a tan solid. The product was dissolved in DCM (2 mL)and treated with TFA (1 mL). The resulting mixture was stirred at roomtemperature for 1 h. The reaction was neutralized with sat. aq. NaHCO₃and the aqueous layer was extracted with DCM (2×). The combined organicextracts were dried over MgSO₄, filtered and concentrated in vacuo toafford Intermediate 18 as a brown oil. (169 mg, 93%)¹H NMR (500 MHz,CDCl₃) δ 8.68 (s, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.92-7.80 (m, 1H),7.45-7.33 (m, 1H), 4.20 (s, 2H), 3.22 (s, 4H), 2.73 (s, 3H).

Example 307-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 18 for Intermediate 9 and2-chloro-3-(trifluoromethyl)benzoic acid for 2,3-dichlorobenzoic acid.MS (ESI): mass calcd. for C₂₁H₁₆ClF₃N₄O, 432.8; m/z found, 433.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.77-8.61 (m, 1H), 8.11-7.98 (m, 1H),7.93-7.84 (m, 1H), 7.82-7.72 (m, 1H), 7.62-7.45 (m, 2H), 7.44-7.33 (m,1H), 5.24-4.87 (m, 1H), 4.64-4.37 (m, 1H), 4.24-3.84 (m, 1H), 3.44-3.15(m, 3H), 2.80-2.68 (m, 3H).

Example 317-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 18 for Intermediate 9. MS (ESI): mass calcd.for C₂₀H₁₆Cl₂N₄O, 398.1; m/z found, 399.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.75-8.62 (m, 1H), 8.10-8.00 (m, 1H), 7.92-7.81 (m, 1H),7.57-7.49 (m, 1H), 7.45-7.34 (m, 1H), 7.32-7.22 (m, 2H), 5.20-4.87 (m,1H), 4.60-4.35 (m, 1H), 4.26-3.87 (m, 1H), 3.55-3.42 (m, 1H), 3.39-3.16(m, 2H), 2.80-2.69 (m, 3H).

Example 327-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 12 for Intermediate 9 and2-chloro-3-(trifluoromethyl)benzoic acid for 2,3-dichlorobenzoic acid.MS (ESI): mass calcd. for C₂₂H₁₂ClF₃N₃O, 431.8; m/z found, 432.1 [M+H]⁺.¹H NMR (500 MHz, MeOD) δ 7.98-7.90 (m, 1H), 7.78-7.71 (m, 1H), 7.71-7.65(m, 1H), 7.65-7.59 (m, 2H), 7.58-7.49 (m, 3H), 5.17-5.05 (m, 1H),4.92-4.85 (s, 1H), 4.14-3.95 (m, 1H), 3.54-3.45 (t, J=5.8 Hz, 1H),3.04-2.98 (t, J=5.9 Hz, 1H), 2.97-2.78 (m, 1H), 2.75-2.59 (m, 3H).

Intermediate 19: tert-butyl2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Intermediate 11 (519 mg, 1.83 mmol),1-(tetrahydropyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (589mg, 2.01 mmol), Pd(Ph₃P)₄ (105 mg, 0.0915 mmol), and 1M aqueous Na₂CO₃(4.57 mL, 4.57 mmol) were combined in dioxane (8 mL) in a round bottomflask and purged with N₂ (g) for 5 minutes. The reaction was capped andheated at 100° C. overnight in an oil bath. The crude mixture waspartitioned between EtOAc/H₂O and extracted with EtOAc (2x). Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated. The product was purified by sgc 0-100% hexane-EtOAcgradient over 8 minutes to afford the desired product (670 mg, 92%). MS(ESI): mass calcd. for C₂₁H₂₉N₅O₃, 399.5; m/z found, 400.3 [M+H]⁺.

Intermediate 20:(2-chloro-3-(trifluoromethyl)phenyl)(2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

Intermediate 19 (1.4 g, 3.50 mmol) was dissolved in DCM (8 mL) andtreated with TFA (2 mL), and stirred at room temp for 1 hour. Thereaction was concentrated and dried under high vacuum. The residue wasthen redissolved in DCM (8 mL) and DIEA (9 mL, 52.5 mmol),2-chloro-3-(trifluoromethyl)benzoic acid (787 mg, 5.50 mmol), and HATU(1.33 g, 3.50 mmol were added. The reaction was stirred at roomtemperature for 1 h and then concentrated in vacuo and purified directlyby sgc using a 0-100% hexane-EtOAc gradient to afford Intermediate 20(506 mg, 29%). MS (ESI): mass calcd. for C₂₄H₂₃ClF₃N₅O₂, 505.9; m/zfound, 506.2 [M+H]⁺.

Example 337-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

TFA (3 mL) was added to a solution of Intermediate 20 (713 mg, 1.40mmol) and triethylsilane (566 μL, 3.52 mmol) in DCM (8 mL). The reactionwas stirred at room temperature for 30 min and then toluene (15 mL) wasadded and the solvents were removed in vacuo. Another portion of toluenewas added and the mixture was reconcentrated and then purified directlyon silica gel eluting with 0-100% hexanes/EtOAc gradient over 12 minutesto obtain the desired product. (506 mg, 85%). (MS (ESI): mass calcd. forC₁₉H₁₅ClF₃N₅O, 421.8; m/z found, 422.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.83-7.66 (m, 2H), 7.57-7.43 (m, 2H), 6.89 (d, J=22.4 Hz, 1H), 5.15-4.90(m, 1H), 4.58-4.33 (m, 1H), 4.29-4.13 (m, 1H), 4.13-3.97 (m, 1H),3.67-3.51 (m, 1H), 3.31-3.22 (m, 1H), 3.23-2.99 (m, 1H), 2.80-2.61 (m,3H).

Example 347-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 33substituting 2,3-dichlorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 20. MS (ESI): mass calcd. for C₁₈H₁₅Cl₂N₅O, 387.1; m/zfound, 388.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75-7.67 (m, 1H),7.58-7.50 (m, 1H), 7.36-7.29 (m, 1H), 7.28-7.20 (m, 1H), 6.93-6.83 (m,1H), 5.12-4.91 (m, 1H), 4.58-4.36 (m, 1H), 4.22-4.02 (m, 1H), 3.64-3.46(m, 1H), 3.27-2.98 (m, 2H), 2.78-2.63 (m, 3H).

Intermediate 21: tert-butyl4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 18substituting 5-tributylstanyl-4-fluoropyrazole for2-tri-n-butylstannylpyridine and omitting the deprotection. MS (ESI):mass calcd. for C₁₆H₂₀FN₅O₂; 333.4; m/z found, 334.2 [M+H]⁺.

Example 357-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 21 for Intermediate 19. MS (ESI): mass calcd.for C₁₉H₁₄ClF₄N₅O, 439.8; m/z found, 440.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.02-7.93 (m, 2H), 7.86-7.76 (m, 1H), 7.72-7.64 (m, 1H),4.97-4.72 (m, 1H), 4.42-4.27 (m, 1H), 4.05-3.87 (m, 1H), 3.52-3.37 (m,2H), 3.14-3.04 (m, 1H), 2.66-2.51 (m, 3H).

Example 367-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 21 for Intermediate 19 and 2,3-dichlorobenzoicacid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.for C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found, 406.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.01-7.92 (m, 1H), 7.78-7.71 (m, 1H), 7.52-7.41 (m, 2H),4.95-4.72 (m, 1H), 4.42-4.25 (m, 1H), 4.07-3.81 (m, 1H), 3.17-2.91 (m,3H), 2.64-2.52 (m, 3H).

Intermediate 22: tert-butyl4-(thiazol-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 18substituting Intermediate 2 for Intermediate 11 and2-tributylstannylthiazole for 2-tri-n-butylstannylpyridine. MS (ESI):mass calcd. for C₁₅H₁₈N₄O₂S, 318.4; m/z found 319.1[M+H]⁺.

Example 377-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 22 for Intermediate 19. MS (ESI): mass calcd.for C₁₈H₁₂ClF₃N₄OS, 424.8; m/z found, 425.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 9.11-8.94 (m, 1H), 8.09-7.95 (m, 1H), 7.82-7.73 (m, 1H),7.61-7.42 (m, 3H), 5.26-4.94 (m, 1H), 4.63-4.40 (m, 1H), 4.24-4.04 (m,1H), 3.74-3.38 (m, 3H).

Example 387-[(2,3-Dichlorophenyl)carbonyl]-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 22 for Intermediate 19 and 2,3-dichlorobenzoicacid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.for C₁₇H₁₂Cl₂N₄OS, 390.0; m/z found, 391.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 9.08-8.93 (m, 1H), 8.08-7.97 (m, 1H), 7.60-7.50 (m, 2H),7.35-7.21 (m, 2H), 5.20-4.96 (m, 1H), 4.63-4.43 (m, 1H), 4.16-4.09 (m,1H), 3.68-3.51 (m, 3H).

Intermediate 23: tert-butyl2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 18substituting 4-(trifluoromethyl)-5-(tributylstannyl)pyrazole for2-tri-n-butylstannylpyridine. MS (ESI): mass calcd. for C₁₇H₂₀F₃N₅O₂,383.4; m/z found 384.2[M+H]⁺.

Example 397-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 23 for Intermediate 19. MS (ESI): mass calcd.for C₂₀H₁₄ClF₆N₅O, 489.8; m/z found, 491.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.01-7.95 (m, 1H), 7.81-7.76 (m, 1H), 7.55-7.45 (m, 2H),5.14-4.91 (m, 1H), 4.60-4.39 (m, 1H), 4.29-4.13 (m, 1H), 4.05-3.89 (m,1H), 3.56-3.40 (m, 1H), 3.24-3.15 (t, J=5.9 Hz, 1H), 3.07-2.88 (m, 1H),2.80-2.63 (m, 3H).

Example 407-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 23 for Intermediate 19 and 2,3-dichlorobenzoicacid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.for C₁₉H₁₄Cl₂F₃N₅O, 455.05; m/z found, 456.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.01-7.95 (m, 1H), 7.56-7.51 (m, 1H), 7.34-7.28 (m, 1H),7.26-7.21 (m, 1H), 5.14-4.92 (m, 1H), 4.62-4.38 (m, 1H), 4.27-4.07 (m,1H), 4.06-3.88 (m, 1H), 3.56-3.40 (m, 1H), 3.23-3.13 (t, J=6.0 Hz, 1H),3.08-2.86 (m, 1H), 2.79-2.59 (m, 3H).

Intermediate 24: tert-butyl4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 12substituting Intermediate 2 for Intermediate 11 and1-(tert-butoxycarbonyl)pyrrole-2-boronic acid for phenylboronic acid.The deprotection was also omitted. MS (ESI): mass calcd. for C₂₁H₂₈N₄O₄,400.5; m/z found, 401.2 [M+H]⁺.

Example 417-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 24 for Intermediate 19 and 2,3-dichlorobenzoicacid for 2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.for C₁₈H₁₄Cl₂N₄O, 372.1; m/z found, 373.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 10.19-9.94 (s, 1H), 8.95-8.75 (m, 1H), 7.59-7.48 (m, 1H),7.37-7.28 (m, 1H), 7.28-7.19 (m, 1H), 7.11-6.99 (m, 1H), 6.89-6.66 (m,1H), 6.46-6.32 (m, 1H), 5.09-4.90 (m, 1H), 4.54-4.34 (m, 1H), 4.22-4.07(t, J=6.0 Hz, 1H), 3.65-3.51 (m, 1H), 3.21-3.09 (m, 1H), 3.06-2.87 (m,1H).

Example 427-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 24 for Intermediate 19. MS (ESI): mass calcd.for C₁₉H₁₄ClF₃N₄O, 406.8; m/z found, 407.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 10.15-9.97 (s, 1H), 8.93-8.76 (m, 1H), 7.84-7.71 (m, 1H),7.58-7.38 (m, 2H), 7.12-7.02 (m, 1H), 6.89-6.68 (m, 1H), 6.48-6.33 (m,1H), 5.12-4.88 (m, 1H), 4.54-4.32 (m, 1H), 4.30-4.03 (m, 1H), 3.69-3.51(m, 1H), 3.19-3.10 (m, 1H), 3.09-2.85 (m, 1H).

Intermediate 25: tert-butyl4-(thiazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 12substituting Intermediate 2 for Intermediate 11 and thiazole-4-boronicacid pinacol ester for phenylboronic acid. The deprotection was alsoomitted. MS (ESI): mass calcd. for C₁₅H₁₈N₄O₂S, 318.4; m/z found, 319.1[M+H]⁺.

Example 437-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 25 for Intermediate 19. MS (ESI): mass calcd.for C₁₈H₁₂ClF₃N₄OS, 424.8; m/z found, 425.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.09-8.85 (m, 2H), 8.45-8.35 (m, 1H), 7.85-7.73 (m, 1H),7.59-7.43 (m, 2H), 5.25-4.92 (m, 1H), 4.66-4.38 (m, 1H), 4.24-3.95 (m,1H), 3.62-3.48 (m, 2H), 3.47-3.24 (m, 1H).

Example 447-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 43substituting intermediate 11 for Intermediate 2 in the synthesis ofIntermediate 25. MS (ESI): mass calcd. for C₁₉H₁₄ClF₃N₄OS, 438.9; m/zfound, 439.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 9.17-9.05 (m, 1H),8.47-8.39 (m, 1H), 7.95-7.90 (m, 1H), 7.75-7.60 (m, 2H), 5.10-4.87 (m,1H), 4.46 (s, 1H), 4.20-3.95 (m, 1H), 3.58-3.48 (m, 1H), 3.41 (t, J=5.9Hz, 1H), 3.29-3.24 (m, 1H), 2.74-2.56 (m, 3H).

Example 457-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 42substituting Intermediate 11 for Intermediate 2 in the synthesis ofIntermediate 24. MS (ESI): mass calcd. for C₂₀H₁₆ClF₃N₄O, 420.8; m/zfound, 421.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.72 (m, 1H),7.57-7.41 (m, 2H), 7.08-7.00 (m, 1H), 6.85-6.66 (m, 1H), 6.45-6.31 (m,1H), 5.08-4.84 (m, 1H), 4.51-4.29 (m, 1H), 4.28-3.97 (m, 1H), 3.67-3.48(m, 1H), 3.17-3.03 (m, 1H), 2.72-2.52 (m, 3H), 2.07-1.93 (m, 1H).

Intermediate 26: tert-butyl4-(3,5-dimethylisoxazol-4-yl)-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 12substituting 3,5-dimethylisoxazole-4-boronic acid for phenylboronic acidand omitting the deprotection step. MS (ESI): mass calcd. forC₁₈H₂₄N₄O₃, 344.4; m/z found, 345.2 [M+H]⁺.

Example 467-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 20substituting Intermediate 26 for Intermediate 19. MS (ESI): mass calcd.for C₂₁H₁₈ClF₃N₄O₂, 450.8; m/z found, 451.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.83-7.75 (m, 1H), 7.57-7.45 (m, 2H), 5.17-4.91 (m, 1H),4.66-4.34 (m, 1H), 4.10-3.96 (m, 1H), 3.78-3.47 (m, 1H), 3.47-3.09 (m,1H), 2.79-2.63 (m, 4H), 2.35 (d, J=19.4 Hz, 3H), 2.22 (d, J=16.3 Hz,3H).

Intermediate 27:(4-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

TFA (1.5 mL) was added to a solution of Intermediate 11 (375 mg, 1.32mmol) in DCM (4 mL). The reaction was stirred at room temperature for 2h and then neutralized with sat. NaHCO₃. The aqueous layer was extractedwith DCM (3×) and the combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo. This residue was dissolved in DCM (3mL) and 2-chloro-3-(trifluoromethyl)benzoic acid (296 mg, 1.32 mmol),TEA (0,367 mL, 2.64 mmol) and HATU (502 mg, 1.32 mmol) were added. Thereaction was stirred overnight at room temperature. The crude mixturewas purified directly using silica gel chromatography eluted withhexanes/EtOAc to afford the title compound as colorless oil. MS (ESI)mass calcd. C₂₁H₁₅ClF₃N₇O₂, 489.8; m/z found 490.1[M+H]⁺.

Example 477-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 22substituting 1H-1,2,3-triazole for pyrazole and Intermediate 27 forIntermediate 2 in Example 22, step a. MS (ESI): mass calcd. forC₁₈H₁₄ClF₃N₆O, 422.8; m/z found, 423.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ3.60-3.48 (m, 1H), 3.38-3.32 (m, 1H), 3.25-3.16 (m, 1H), 2.78-2.61 (m,3H), 4.20-3.98 (m, 1H), 8.16-8.08 (m, 2H), 7.96-7.91 (m, 1H), 7.77-7.69(m, 1H), 7.68-7.62 (m, 1H), 5.17-4.90 (m, 2H).

Example 487-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 22substituting 1H-1,2,3-triazole for pyrazole and Intermediate 27 forIntermediate 2 in Example 22, step a. MS (ESI): mass calcd. forC₁₈H₁₄ClF₃N₆O, 422.8; m/z found, 423.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ8.83-8.79 (m, 1H), 7.95-7.90 (m, 2H), 7.77-7.61 (m, 2H), 5.20-4.91 (m,2H), 4.22-4.00 (m, 1H), 3.63-3.52 (m, 1H), 3.44-3.36 (m, 1H), 3.29-3.19(m, 1H), 2.77-2.62 (m, 3H).

Example 497-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-isoxazol-4-yl-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 46substituting 4-isoxazoleboronic acid pinacol ester for3,5-dimethylisoxazole-4-boronic acid in the synthesis of Intermediate26. MS (ESI): mass calcd. for C₁₉H₁₄ClF₃N₄O₂, 422.8; m/z found, 423.1[M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 9.43-9.28 (m, 1H), 9.08-9.00 (m, 1H),7.97-7.90 (m, 1H), 7.77-7.60 (m, 2H), 5.14-5.03 (m, 1H), 4.47-4.39 (s,1H), 4.29-4.03 (m, 1H), 3.65-3.55 (m, 1H), 3.16-3.04 (m, 1H), 3.03-2.89(m, 1H), 2.72-2.57 (m, 3H).

Example 507-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 43substituting 3,5-dimethylisoxazole-4-boronic acid for thiazole-4-boronicacid pinacol ester in the synthesis of Intermediate 25. MS (ESI): masscalcd. for C₂₀H₁₆ClF₃N₄O₂, 436.8; m/z found, 437.1 [M+H]⁺. ¹H NMR (500MHz, MeOD) δ 9.09-8.96 (m, 1H), 7.96-7.88 (m, 1H), 7.76-7.69 (m, 1H),7.69-7.61 (m, 1H), 5.16-4.90 (m, 1H), 4.60-4.45 (m, 1H), 4.18-3.96 (m,1H), 3.65-3.48 (m, 1H), 2.93-2.81 (m, 1H), 2.77-2.66 (m, 1H), 2.41-2.30(m, 3H), 2.26-2.12 (m, 3H).

Example 517-{[2-Fluoro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 33substituting 2-fluoro-3-(trifluoromethyl)benzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 20. MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.4; m/zfound, 406.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.98-7.80 (m, 3H),7.59-7.49 (m, 1H), 6.97 (s, 1H), 4.92-4.76 (m, 1H), 4.55-4.41 (m, 1H),4.06-3.91 (m, 1H), 3.56 (t, J=5.7 Hz, 1H), 3.27-3.09 (m, 2H), 2.67-2.52(m, 3H).

Example 522-Methyl-7-{[2-methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 33substituting 2-methyl-3-(trifluoromethyl)benzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 20. MS (ESI): mass calcd. for C₂₀H₁₈F₃N₅O, 401.4; m/zfound, 402.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.75-7.64 (m, 2H),7.46-7.32 (m, 2H), 6.95-6.84 (m, 1H), 5.20-4.83 (m, 1H), 4.48-4.34 (m,1H), 4.23-4.05 (m, 1H), 3.62-3.42 (m, 1H), 3.32-3.16 (m, 1H), 3.12-2.98(m, 1H), 2.70 (d, J=47.3 Hz, 3H), 2.49-2.29 (m, 3H).

Example 537-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 33substituting 2,4-dichloro-3-fluorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 20. MS (ESI): mass calcd. for C₁₈H₁₄Cl₂FN₅O, 405.1; m/zfound, 406.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.77-7.66 (m, 1H),7.47-7.35 (m, 1H), 7.16-7.06 (m, 1H), 6.97-6.80 (m, 1H), 5.12-4.90 (m,1H), 4.59-4.34 (m, 1H), 4.20-4.00 (m, 1H), 3.65-3.47 (m, 1H), 3.35-2.99(m, 2H), 2.80-2.59 (m, 3H).

Example 547-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 33substituting Intermediate 8 for Intermediate 11 in the synthesis ofIntermediate 19. MS (ESI): mass calcd. for C₂₀H₁₈ClF₃N₆O, 450.8; m/zfound, 451.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J=7.8 Hz, 1H),7.89-7.75 (m, 2H), 7.73-7.60 (m, 1H), 6.95 (s, 1H), 4.85-4.56 (m, 1H),4.27-4.09 (m, 1H), 4.06-3.79 (m, 1H), 3.50-3.35 (m, 1H), 3.22-2.98 (m,7H), 2.93-2.70 (m, 1H).

Intermediate 28:7-benzyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Intermediate 16substituting 1-(tetrahydropyran-2-yl)-1h-pyrazole-5-boronic acid pinacolester for phenylboronic acid. MS (ESI): mass calcd. for C₂₂H₂₆N₆O,390.5; m/z found, 391.2 [M+H]⁺.

Intermediate 29:4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Intermediate 17substituting Intermediate 28 for Intermediate 16. MS (ESI): mass calcd.for C₁₅H₂₀N₆O, 300.4; m/z found, 301.2 [M+H]⁺.

Intermediate 30:(2-amino-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 29 for Intermediate 9. MS (ESI): mass calcd.for C₂₃H₂₂ClF₃N₆O₂, 506.9; m/z found, 507.2 [M+H]⁺.

Example 557-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 33substituting Intermediate 30 for Intermediate 19. MS (ESI): mass calcd.for C₁₈H₁₄ClF₃N₆O, 422.8; m/z found, 423.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.86-7.74 (m, 1H), 7.70-7.60 (m, 1H), 7.59-7.43 (m, 2H),6.83-6.72 (m, 1H), 4.99-4.68 (m, 1H), 4.40-4.18 (m, 1H), 4.16-3.95 (m,1H), 3.63-3.44 (m, 2H), 3.18-2.86 (m, 2H).

Intermediate 31: ethyl 4-((1-phenylethyl)amino)pentanoate

NaBH(OAc)₃ (5.97 g, 28.19 mmol) was added to a solution of ethyllevulinate (2 mL, 14.10 mmol) and DL-alpha-methylbenzylamine (1.85 mL,14.10 mmol) in DCE (25 mL). The reaction was stirred at ambienttemperature overnight. The reaction mixture was partitioned between sat.NaHCO₃ solution and DCM. The aqueous layer was extracted with DCM (3×)and the combined organic extracts were dried over MgSO₄ filtered andconcentrated to isolate Intermediate 31 as a pale yellow oil (3.16 g,90%). MS (ESI): mass calcd. for C₁₅H₂₃NO₂, 249.3; m/z found, 250.2[M+H]⁺.

Intermediate 32: ethyl4-((2-ethoxy-2-oxoethyl)(1-phenylethyl)amino)pentanoate

NaBH(OAc)₃ (5.37 g, 25.34 mmol) was added to a solution of Intermediate31 (3.16 g, 12.67 mmol) and glyoxylic acid ethyl ester (2.56 mL, 25.34mmol) in DCE (25 mL). The reaction was stirred at ambient temperatureovernight. The reaction mixture was partitioned between sat. NaHCO₃solution and DCM. The aqueous layer was extracted with DCM (3x) and thecombined organic extracts were dried over MgSO₄ filtered andconcentrated to isolate Intermediate 32 as a pale yellow oil (4.22 g,99%). MS (ESI): mass calcd. for C₁₉H₂₉NO₄, 335.4; m/z found, 336.2[M+H]⁺.

Intermediate 33: ethyl2-methyl-5-oxo-1-(1-phenylethyl)piperidine-4-carboxylate

KOtBu (11.26 g, 100 mmol) was added to a solution of Intermediate 32(20.2 g, 60 mmol) in toluene (100 mL). The reaction was stirred atambient temperature for 3 hours and then concentrated in vacuo. Thecrude mixture was partitioned between DCM and sat NH₄Cl solution and theaqueous layer was extracted with DCM (3×). The combined organic extractswere washed with sat. NaCl solution and H₂O and then dried over MgSO₄.Celite was added and the organic extracts were filtered and concentratedin vacuo. The crude material was purified by chromatography on SiO₂ andeluted with EtOAc/hexane to afford Intermediate 33 (11.1 g, 64%). MS(ESI): mass calcd. for C₁₇H₂₃NO₃, 289.4; m/z found, 290.2 [M+H]⁺.

Intermediate 34:2,6-dimethyl-7-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

The title compound was prepared in a manner analogous to Intermediate 10substituting Intermediate 33 for ethylN—BOC-3-oxopiperidine-4-carboxylate. MS (ESI): mass calcd. for C₁₇H₂₁N₃O283.4; m/z found, 284.2 [M+H]⁺.

Intermediate 35: tert-butyl4-hydroxy-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

Intermediate 34 (1.1 g, 3.88 mmol) was dissolved in MeOH (15 mL) and THF(15 mL). Ammonium formate (1.24 g, 19.4 mmol), BOC anhydride (1.27 g,5.82 mmol) and 10% Pd/C (413 mg, 0.388 mmol) were added and the reactionwas heated to reflux overnight. The crude reaction was filtered througha pad of celite and the filtrate was concentrated in vacuo. Intermediate35 was obtained by purification on SiO₂ eluting with EtOAc/hexane (890mg, 82%). MS (ESI): mass calcd. for C₁₄H₂₁N₃O₃, 279.3; m/z found, 280.2[M+H]⁺.

Intermediate 36: tert-butyl4-chloro-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 11substituting Intermediate 35 for Intermediate 10. MS (ESI): mass calcd.for C₁₄H₂₀ClN₃O₂ 297.8; m/z found, 298.1 [M+H]⁺.

Example 567-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 33substituting Intermediate 36 for Intermediate 11 in the synthesis ofIntermediate 19. MS (ESI): mass calcd. for C₂₀H₁₇ClF₃N₅O, 435.8; m/zfound, 436.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 7.96-7.90 (m, 1H),7.79-7.71 (m, 2H), 7.70-7.59 (m, 1H), 7.05-6.95 (s, 1H), 5.53-5.32 (m,1H), 4.64-4.37 (m, 1H), 4.33-3.97 (m, 1H), 3.50-3.34 (m, 2H), 3.30-3.19(s, 1H), 2.66-2.56 (m, 2H), 1.35-1.05 (m, 3H).

Intermediate 37: tert-butyl4-chloro-2-cyclopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 11substituting cyclopropylcarbamidine hydrochloride for acetamidinehydrochloride in the synthesis of Intermediate 10. MS (ESI): mass calcd.for C₁₅H₂₀ClN₃O₂ 309.8; m/z found, 310.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃)δ 4.54 (s, 2H), 3.69 (t, J=5.7 Hz, 2H), 2.79 (s, 2H), 2.23-2.10 (m, 1H),1.49 (s, 9H), 1.16-0.99 (m, 4H).

Example 577-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-cyclopropyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 33substituting Intermediate 37 for Intermediate 11 in the synthesis ofIntermediate 19. MS (ESI): mass calcd. for C₂H₁₇ClF₃N₅O, 447.8; m/zfound, 448.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.82-7.75 (m, 1H),7.74-7.65 (m, 1H), 7.56-7.43 (m, 2H), 6.89-6.79 (m, 1H), 5.13-4.84 (m,1H), 4.54-4.31 (m, 1H), 4.27-3.98 (m, 2H), 3.65-3.45 (m, 1H), 3.26-2.94(m, 2H), 2.33-2.08 (m, 1H), 1.29-1.00 (m, 4H).

Example 58(6R*)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 56 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% MeOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.66 min retention time). MS (ESI): mass calcd. forC₂₀H₁₇ClF₃N₅O, 435.8; m/z found, 436.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ7.83-7.74 (m, 1H), 7.74-7.66 (m, 1H), 7.56-7.40 (m, 2H), 6.96-6.82 (m,1H), 5.69-5.46 (m, 1H), 4.68-4.37 (m, 1H), 4.36-4.25 (m, 1H), 3.44-3.25(m, 1H), 3.24-2.90 (m, 1H), 2.80-2.57 (m, 3H), 1.35-1.09 (m, 3H).

Example 59(6S*)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound, absolute configuration unknown, was obtained as asingle enatiomer by Chiral SFC purification of Example 56 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% MeOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (99.1% singleenantiomer, 4.55 min retention time). MS (ESI): mass calcd. forC₂₀H₁₇ClF₃N₅O, 435.1; m/z found, 435.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ7.84-7.75 (m, 1H), 7.75-7.67 (m, 1H), 7.57-7.41 (m, 2H), 6.95-6.83 (m,1H), 5.66-5.52 (m, 1H), 4.68-4.36 (m, 1H), 4.36-4.25 (m, 1H), 3.41-3.26(m, 1H), 3.24-2.96 (m, 1H), 2.79-2.64 (m, 3H), 1.32-1.10 (m, 3H).

Intermediate 38:7-benzyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 12substituting7-benzyl-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinefor Intermediate 11 and 1-(tetrahydropyran-2-yl)-1h-pyrazole-5-boronicacid pinacol ester for phenylboronic acid. MS (ESI): mass calcd. forC₂₃H₂₄F₃N₅O, 443.2; m/z found, 444.2 [M+H]⁺.

Intermediate 39:4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 17substituting Intermediate 38 for Intermediate 16. MS (ESI): mass calcd.for C₁₆H₁₈F₃N₅O, 353.3; m/z found, 354.2 [M+H]⁺.

Intermediate 40:(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 25substituting Intermediate 39 for Intermediate 9. MS (ESI): mass calcd.for C₂₄H₂₀ClF₆N₅O₂, 559.1; m/z found, 476.1 [M-THP]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.89-7.77 (m, 1H), 7.74-7.62 (m, 1H), 7.57-7.45 (m, 2H),6.72-6.53 (m, 1H), 6.09-5.93 (m, 1H), 5.45 (d, J=20.1 Hz, 1H), 4.95-4.83(m, 1H), 4.76-4.51 (m, 1H), 3.87 (t, J=10.5 Hz, 1H), 3.72-3.51 (m, 1H),3.51-3.34 (m, 1H), 3.24-3.02 (m, 1H), 3.01-2.87 (m, 1H), 2.51-2.33 (m,1H), 2.25-2.03 (m, 2H), 1.74-1.48 (m, 3H).

Example 60(4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 33substituting Intermediate 40 for Intermediate 20. MS (ESI): mass calcd.for C₁₉H₁₂ClF₆N₅O, 475.1; m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz,MeOD) δ 7.96-7.89 (m, 1H), 7.79-7.60 (m, 3H), 7.19-7.12 (m, 1H),5.23-4.95 (m, 2H), 4.57 (s, 1H), 4.26-4.07 (m, 1H), 3.67-3.54 (m, 2H).

Example 613-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methylbenzonitrile

The title compound was prepared in a manner analogous to Example 74substituting 3-cyano-2-methylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI) mass calcd. C₂₁H₂₀N₆O, 372.2; m/z found 373.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.17 (br s, 1H), 7.79-7.20 (m, 4H),7.04-6.77 (m, 1H), 5.66-5.46 (m, 1H), 4.58-3.94 (m, 2H), 3.43-2.95 (m,2H), 2.83-2.09 (m, 6H), 1.45-1.05 (m, 3H).

Example 62(2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 56substituting imidoformamide acetate for acetamidine hydrochloride in thesynthesis of Intermediate 34. MS (ESI): mass calcd. for C₁₉H₁₅ClF₃N₅O,421.1; m/z found, 422.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.12-8.94 (m,1H), 7.84-7.76 (m, 1H), 7.76-7.67 (m, 1H), 7.61-7.38 (m, 2H), 7.01-6.90(m, 1H), 5.74-5.51 (m, 1H), 4.72-4.42 (m, 1H), 4.41-4.03 (m, 1H),3.48-3.06 (m, 2H), 1.35-1.08 (m, 3H).

Example 63(2-amino-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 56substituting guanidine carbonate for acetamidine hydrochloride in thesynthesis of Intermediate 34. MS (ESI): mass calcd. for C₁₉H₁₆ClF₃N₆O,436.1; m/z found, 437.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.82-7.74 (m,1H), 7.72-7.64 (m, 1H), 7.55-7.42 (m, 2H), 6.86-6.71 (m, 1H), 5.13-4.86(m, 2H), 4.51-4.22 (m, 1H), 4.20-3.97 (m, 1H), 3.30-3.17 (m, 1H),1.32-1.07 (m, 3H).

Example 64(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 56substituting 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.C₂₀H₁₆ClF₄N₅O, 453.1; m/z found, 454.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ8.02-7.77 (m, 1H), 7.76-7.64 (m, 1H), 7.55-7.38 (m, 1H), 7.01 (s, 1H),5.51-5.26 (m, 1H), 4.64-4.36 (m, 1H), 4.32-3.98 (m, 1H), 3.52-3.35 (m,1H), 3.27-3.17 (m, 1H), 2.74-2.58 (m, 3H), 1.40-1.01 (m, 3H).

Example 65(S*)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enatiomer by Chiral SFC purification of Example 64 performedusing an irregular SiOH 15-40 μm, 300 g MERCK column and a mobile phaseof 70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed byanalytical SFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of70% CO₂, 30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.20 min retention time). MS (ESI): mass calcd.C₂₀H₁₆ClF₄N₅O, 453.1; m/z found, 453.7 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.75-7.67 (m, 1H), 7.55-7.40 (m, 1H), 7.25-7.14 (m, 1H), 6.94-6.82 (m,1H), 5.68-5.43 (m, 1H), 4.70-4.34 (m, 1H), 4.36-3.99 (m, 1H), 3.43-3.24(m, 1H), 3.23-2.97 (m, 1H), 2.81-2.60 (m, 3H), 1.32-1.07 (m, 3H).

Example 66(R*)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 64 performedusing an irregular SiOH 15-40 μm, 300 g MERCK column and a mobile phaseof 70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed byanalytical SFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of70% CO₂, 30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 2.42 min retention time). MS (ESI): mass calcd.C₂₀H₁₆ClF₄N₅O, 453.1; m/z found, 453.7 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.78-7.66 (m, 1H), 7.55-7.39 (m, 1H), 7.26-7.16 (m, 1H), 6.94-6.83 (m,1H), 5.66-5.43 (m, 1H), 4.70-4.35 (m, 1H), 4.34-3.99 (m, 1H), 3.42-3.21(m, 1H), 3.22-2.96 (m, 1H), 2.83-2.60 (m, 3H), 1.37-1.05 (m, 3H).

Example 67(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 56substituting 2,3-dichlorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.C₁₉H₁₇C₁₂N₅O, 401.1; m/z found, 402.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ7.80-7.69 (m, 1H), 7.70-7.64 (m, 1H), 7.51-7.28 (m, 2H), 7.06-6.89 (m,1H), 5.50-5.28 (m, 1H), 4.62-4.38 (m, 1H), 4.35-4.00 (m, 1H), 3.46-3.35(m, 1H), 3.29-3.17 (m, 1H), 2.77-2.53 (m, 3H), 1.30-1.03 (m, 3H).

Example 68(R*)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 67 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 4.00 min retention time). MS (ESI): mass calcd.C₁₉H₁₇Cl₂N₅O, 401.1; m/z found, 401.7 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.76-7.67 (m, 1H), 7.57-7.48 (m, 1H), 7.37-7.27 (m, 1H), 7.25-7.15 (m,1H), 6.92-6.80 (m, 1H), 5.71-5.46 (m, 1H), 4.67-4.25 (m, 2H), 4.15-4.02(m, 1H), 3.42-3.23 (m, 1H), 3.18-2.89 (m, 1H), 2.83-2.61 (m, 3H),1.35-1.07 (m, 3H).

Example 69(S*)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 67 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (98.2% singleenantiomer, 4.72 min retention time). MS (ESI): mass calcd.C₁₉H₁₇Cl₂N₅O, 401.1; m/z found, 401.7 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.76-7.67 (m, 1H), 7.57-7.48 (m, 1H), 7.37-7.27 (m, 1H), 7.25-7.15 (m,1H), 6.92-6.80 (m, 1H), 5.71-5.46 (m, 1H), 4.67-4.25 (m, 2H), 4.15-4.02(m, 1H), 3.42-3.23 (m, 1H), 3.18-2.89 (m, 1H), 2.83-2.61 (m, 3H),1.35-1.07 (m, 3H).

Example 70(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 56substituting 2,4-dichloro-3-fluorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.C₁₉H₁₆Cl₂FN₅O, 419.1; m/z found, 420.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ7.74 (d, J=13.5 Hz, 1H), 7.67-7.51 (m, 1H), 7.34-7.18 (m, 1H), 7.00 (s,1H), 5.53-5.27 (m, 1H), 4.64-4.36 (m, 1H), 4.36-4.00 (m, 1H), 3.43-3.36(m, 1H), 3.29-3.18 (m, 1H), 2.77-2.49 (m, 3H), 1.36-1.00 (m, 3H).

Example 71(R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 70 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 30% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 3.56 minretention time). MS (ESI): mass calcd. C₁₉H₁₆Cl₂FN₅O, 419.1; m/z found,419.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.75-7.67 (m, 1H), 7.47-7.34 (m,1H), 7.14-7.01 (m, 1H), 6.88 (d, J=25.9 Hz, 1H), 5.65-5.44 (m, 1H),4.70-4.37 (m, 1H), 4.36-4.03 (m, 1H), 3.42-3.21 (m, 1H), 3.23-2.92 (m,1H), 2.81-2.61 (m, 3H), 1.35-1.04 (m, 3H).

Example 72(S)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 70 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (99% single enantiomer,4.26 min retention time). MS (ESI): mass calcd. C₁₉H₁₆Cl₂FN₅O, 419.1;m/z found, 419.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.77-7.66 (m, 1H),7.50-7.32 (m, 1H), 7.16-7.01 (m, 1H), 6.95-6.82 (m, 1H), 5.67-5.46 (m,1H), 4.71-4.37 (m, 1H), 4.35-4.02 (m, 1H), 3.33 (dd, J=10.7, 5.7 Hz,1H), 3.25-2.94 (m, 1H), 2.80-2.56 (m, 3H), 1.38-1.04 (m, 3H).

Example 73(2-chloro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 56substituting 1-methyl-1H-pyrazole-5-boronic acid pinacol ester for1-(tetrahydropyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester. MS(ESI): mass calcd. for C₂₁H₁₉ClF₃N₅O, 449.1; m/z found, 450.2 [M+H]⁺.$Unable to interpret NMR$

Intermediate 41:4-chloro-2,6-dimethyl-7-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 11substituting Intermediate 34 for Intermediate 10. MS (ESI): mass calcd.for C₁₇H₂₀ClN₃ 301.1; m/z found, 302.1 [M+H]⁺.

Intermediate 42:2,6-dimethyl-7-(1-phenylethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 19substituting Intermediate 41 for Intermediate 11. MS (ESI): mass calcd.for C₂₅H₃₁N₅O 417.3; m/z found, 418.3 [M+H]⁺.

Intermediate 43:2,6-dimethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 42 (3.76 g, 9.00 mmol) was dissolved in MeOH (40 mL) andTHF (40 mL). Ammonium formate (2.86 g, 45 mmol) and 10% Pd/C (958 mg,0.900 mmol) were added and the reaction was heated to reflux overnight.The crude reaction mixture was filtered through a pad of celite and thefiltrate was concentrated in vacuo to afford Intermediate 43 (2.98 g,99%). MS (ESI): mass calcd. for C₁₇H₂₃N₅O, 313.2; m/z found, 314.2[M+H]⁺.

Intermediate 44: 2-fluoro-3-(trifluoromethyl)benzoyl chloride

Oxalyl chloride (0.488 mL, 5.76 mmol) was added to a suspension of2-fluoro-3-(trifluoromethyl)benzoic acid (1.00 g, 4.81 mmol) in DCM (10mL) containing catalytic DMF. The reaction was stirred at roomtemperature for 90 minutes and solvents were removed in vacuo to affordthe desired compound (1.08 g, 99%). The product was used withoutadditional purification.

Intermediate 45: 2-chloro-3-(trifluoromethyl)benzoyl chloride

The title compound was prepared in a manner analogous to Intermediate 44substituting 2-chloro-3-(trifluoromethyl)benzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid. The product was used as iswithout additional purification.

Example 74(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone

Intermediate 43 (284 mg, 1.26 mmol) was added to a solution ofIntermediate 44 (395 mg, 1.26 mmol) and DIPEA (0.434 mL, 2.52 mmol) inDCM (10 mL). The reaction was stirred at room temperature for one hour.The crude mixture was treated directly with TFA (1.1 mL) andtriethylsilane (0.202 mL, 1.26 mmol) and stirred for 30 minutes. Thesolvents were removed in vacuo and the crude mixture was purified bychromatography on a Prep Agilent system with a XBridge C18 OBD 50×100 mmcolumn eluting with 5 to 99% (0.05% NH₄OH in H₂O)/ACN over 17 min toafford the desired product (256 mg, 46%). MS (ESI): mass calcd. forC₂₀H₁₂F₄N₅O, 419.1; m/z found, 420.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ7.98-7.80 (m, 3H), 7.61-7.49 (m, 1H), 6.98 (s, 1H), 5.35-5.16 (m, 1H),4.66-4.34 (m, 1H), 4.33-3.99 (m, 1H), 3.61-3.29 (m, 2H), 2.67-2.53 (m,3H), 1.23-1.02 (m, 3H).

Example 75(R*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 74 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4 6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.34 min retention time). MS (ESI): mass calcd. forC₂₀H₁₂F₄N₅O, 419.1; m/z found, 419.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.00-7.80 (m, 3H), 7.62-7.47 (m, 1H), 6.99 (s, 1H), 5.25 (d, J=19.3 Hz,1H), 4.67-4.33 (m, 1H), 4.31-4.01 (m, 1H), 3.52-3.36 (m, 1H), 3.30-3.07(m, 1H), 2.72-2.52 (m, 3H), 1.27-1.01 (m, 3H).

Example 76(S*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 74 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (98% single enantiomer,3.80 min retention time). MS (ESI): mass calcd. for C₂₀H₁₇F₄N₅O, 419.1;m/z found, 419.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.97-7.84 (m, 3H),7.62-7.50 (m, 1H), 6.99 (s, 1H), 5.35-5.15 (m, 1H), 4.68-4.39 (m, 1H),4.37-4.21 (m, 1H), 4.16-3.95 (m, 1H), 3.51-3.36 (m, 1H), 2.75-2.52 (m,3H), 1.27-0.99 (m, 3H).

Example 77(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2-methyl-3(trifluoromethyl)benzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₂₁H₂₀F₃N₅O, 415.2; m/zfound, 416.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.79 (d,J=7.9 Hz, 1H), 7.70-7.59 (m, 1H), 7.60-7.42 (m, 1H), 6.98 (s, 1H),5.39-5.18 (m, 1H), 4.58-4.27 (m, 1H), 4.17-3.79 (m, 1H), 3.31-3.05 (m,2H), 2.74-2.52 (m, 3H), 2.46-2.08 (m, 3H), 1.26-0.94 (m, 3H).

Example 78(R*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 77 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of78% CO₂, 22% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 80% CO₂,20% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 4.81 min retention time). MS (ESI): mass calcd. forC₂₁H₂₀F₃N₅O, 415.2; m/z found, 415.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.74-7.64 (m, 2H), 7.46-7.28 (m, 2H), 6.96-6.82 (m, 1H), 5.69-5.53 (m,1H), 4.47-4.03 (m, 2H), 3.40-3.07 (m, 2H), 2.80-2.73 (s, 1H), 2.72-2.61(m, 2H), 2.54-2.23 (m, 3H), 1.32-1.11 (m, 3H).

Example 79(S*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 77 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of78% CO₂, 22% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 80% CO₂,20% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 6.03 min retention time). MS (ESI): mass calcd. forC₂₁H₂₀F₃N₅O, 415.2; m/z found, 415.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.75-7.65 (m, 2H), 7.45-7.29 (m, 2H), 6.93-6.82 (m, 1H), 5.72-5.53 (m,1H), 4.49-4.36 (m, 1H), 4.34-4.02 (m, 1H), 3.45-3.22 (m, 1H), 3.20-2.97(m, 1H), 2.80-2.63 (m, 3H), 2.55-2.21 (m, 3H), 1.33-1.10 (m, 3H).

Example 80(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2,3-dichloro-4-fluorobenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₁₉H₁₆Cl₂FN₅O, 419.1; m/zfound, 420.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.68-7.44(m, 2H), 6.97 (s, 1H), 5.33-5.15 (m, 1H), 4.55-4.26 (m, 1H), 4.25-3.91(m, 2H), 3.28-3.18 (m, 1H), 2.73-2.52 (m, 3H), 1.26-0.92 (m, 3H).

Example 81(R*)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 80 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.83 min retention time). MS (ESI): mass calcd. forC₁₉H₁₆Cl₂FN₅O, 419.1; m/z found, 419.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.75-7.67 (m, 1H), 7.26-7.12 (m, 2H), 6.93-6.82 (m, 1H), 5.68-5.45 (m,1H), 4.68-4.36 (m, 1H), 4.35-4.01 (m, 1H), 3.46-3.25 (m, 1H), 3.23-2.92(m, 1H), 2.80-2.61 (m, 3H), 1.36-1.08 (m, 3H).

Example 82(S*)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 80 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂,30% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 4.92 min retention time). MS (ESI): mass calcd. forC₁₉H₁₆Cl₂FN₅O, 419.1; m/z found, 419.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.75-7.67 (m, 1H), 7.24-7.11 (m, 2H), 6.94-6.82 (m, 1H), 5.68-5.46 (m,1H), 4.68-4.36 (m, 1H), 4.36-4.04 (m, 1H), 3.42-3.25 (m, 1H), 3.16-2.92(m, 1H), 2.80-2.61 (m, 3H), 1.32-1.08 (m, 3H).

Example 83(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2,4-dichlorobenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₁₉H₁₇Cl₂N₅O, 401.1; m/zfound, 402.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.91-7.69 (m, 2H),7.62-7.40 (m, 2H), 6.97 (s, 1H), 5.31-5.17 (m, 1H), 4.55-4.25 (m, 1H),4.20-3.88 (m, 1H), 3.27-3.08 (m, 2H), 2.66-2.52 (m, 3H), 1.22-0.99 (m,3H).

Example 84(R*)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 83 performedusing a CHIRALPAK AD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD (250×4 6 mm) and amobile phase of 70% CO₂, 30% iPrOH containing 0.3% iPrNH₂ over 7minutes. (100% single enantiomer, 3.21 min retention time). MS (ESI):mass calcd. for C₁₉H₁₇Cl₂N₅O, 401.1; m/z found, 401.8 [M+H]⁺.

Example 85(S*)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 83 performedusing a CHIRALPAK AD-H (5 μm, 250×20 mm) column and a mobile phase of70% CO₂, 30% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD (250×4 6 mm) and amobile phase of 70% CO₂, 30% iPrOH containing 0.3% iPrNH₂ over 7minutes. (97% single enantiomer, 3.67 min retention time). MS (ESI):mass calcd. for C₁₉H₁₇Cl₂N₅O, 401.1; m/z found, 401.8 [M+H]⁺.

Example 86(2,5-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2,5-dichlorobenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₁₉H₁₇Cl₂N₅O, 401.1; m/zfound, 402.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO) δ 7.91-7.82 (s, 1H),7.75-7.68 (m, 1H), 7.68-7.61 (m, 1H), 7.60-7.55 (m, 1H), 7.01-6.93 (s,1H), 5.34-5.17 (m, 1H), 4.58-4.28 (m, 1H), 4.21-3.91 (m, 1H), 3.27-3.14(m, 2H), 2.68-2.53 (m, 3H), 1.26-1.02 (m, 3H).

Example 87(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

4-chloro-2-fluorobenzoic acid (171 mg, 0.957 mmol) and HATU (364, 0.957mmol) were added to a solution of Intermediate 43 (300 mg, 0.957 mmol)and DIEA (0.495 mL, 2.87 mmol) in DCM (10 mL). The reaction was stirredat room temperature for one hour. The crude mixture was treated directlywith TFA (2.0 mL) and triethylsilane (0.289 mL, 1.80 mmol) and stirredfor 30 minutes. The solvents were removed in vacuo and the crude mixturewas purified by chromatography on a Prep Agilent system with a XBridgeC18 OBD 50×100 mm column eluting with 5 to 99% (0.05% NH₄OH in H₂O)/ACNover 17 min to afford the desired product (143 mg, 38%). MS (ESI): masscalcd. for C₁₉H₁₇ClFN₅O, 385.1; m/z found, 386.0 [M+H]⁺. ¹H NMR (400MHz, DMSO) δ 7.93-7.84 (s, 1H), 7.67-7.48 (m, 2H), 7.48-7.38 (m, 1H),7.02-6.93 (s, 1H), 5.31-5.14 (m, 1H), 4.60-4.30 (m, 1H), 4.30-4.05 (m,1H), 3.32-3.07 (m, 2H), 2.70-2.53 (m, 3H), 1.21-1.01 (m, 3H).

Example 88(R*)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 87 performedusing a CHIRALPAK AD-H (5 μm, 250×20 mm) column and a mobile phase of65% CO₂, 35% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 60% CO₂,40% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 2.17 min retention time). MS (ESI): mass calcd. forC₁₉H₁₇ClFN₅O, 385.1; m/z found, 385.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.75-7.67 (m, 1H), 7.42-7.31 (m, 1H), 7.25-7.13 (m, 2H), 6.92-6.80 (m,1H), 5.60-5.42 (m, 1H), 4.66-4.16 (m, 2H), 3.38-3.25 (m, 1H), 3.12-2.93(m, 1H), 2.80-2.59 (m, 3H), 1.32-1.11 (m, 3H).

Example 89(S*)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 87 performedusing a CHIRALPAK AD-H (5 μm, 250×20 mm) column and a mobile phase of65% CO₂, 35% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 60% CO₂,40% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (99% single enantiomer,2.50 min retention time). MS (ESI): mass calcd. for C₁₉H₁₇ClFN₅O, 385.1;m/z found, 385.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75-7.66 (m, 1H),7.41-7.31 (m, 1H), 7.25-7.13 (m, 2H), 6.92-6.80 (m, 1H), 5.61-5.41 (m,1H), 4.66-4.16 (m, 2H), 3.48-3.21 (m, 1H), 3.15-2.94 (m, 1H), 2.79-2.62(m, 3H), 1.32-1.10 (m, 3H).

Example 90(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 87substituting 2-chloro-4-fluorobenzoic acid for 4-chloro-2-fluorobenzoicacid. MS (ESI): mass calcd. for C₁₉H₁₇ClFN₅O, 385.1; m/z found, 386.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 (s, 1H), 7.67-7.52 (m, 2H),7.51-7.28 (m, 1H), 6.97 (s, 1H), 5.34-5.14 (m, 1H), 4.56-4.26 (m, 1H),4.18-3.86 (m, 1H), 3.29-3.11 (m, 2H), 2.71-2.52 (m, 3H), 1.24-0.96 (m,3H).

Example 91(R*)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 90 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of65% CO₂, 35% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALCEL OD-H (250×4 6 mm) and amobile phase of 70% CO₂, 30% iPrOH containing 0.3% iPrNH₂ over 7minutes. (100% single enantiomer, 3.11 min retention time). MS (ESI):mass calcd. for C₁₉H₁₇ClFN₅O, 385.1; m/z found, 385.8 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.75-7.67 (m, 1H), 7.39-7.28 (m, 1H), 7.26-7.18 (m,1H), 7.16-6.99 (m, 1H), 6.92-6.82 (m, 1H), 5.70-5.45 (m, 1H), 4.72-4.36(m, 1H), 4.37-4.07 (m, 1H), 3.43-3.20 (m, 1H), 3.16-2.92 (m, 1H),2.78-2.60 (m, 3H), 1.31-1.07 (m, 3H).

Example 92(S*)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 90 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of65% CO₂, 35% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALCEL OD-H (250×4 6 mm) and amobile phase of 70% CO₂, 30% iPrOH containing 0.3% iPrNH₂ over 7minutes. (99% single enantiomer, 3.80 min retention time). MS (ESI):mass calcd. for C₁₉H₁₇ClFN₅O, 385.1; m/z found, 385.8 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.76-7.66 (m, 1H), 7.40-7.28 (m, 1H), 7.25-7.17 (m,1H), 7.16-7.00 (m, 1H), 6.93-6.81 (m, 1H), 5.74-5.44 (m, 1H), 4.66-4.37(m, 1H), 4.36-4.07 (m, 1H), 3.47-3.23 (m, 1H), 3.20-2.90 (m, 1H),2.82-2.57 (m, 3H), 1.34-1.04 (m, 3H).

Example 93(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 87substituting 2,4-difluorobenzoic acid for 4-chloro-2-fluorobenzoic acid.MS (ESI): mass calcd. for C₁₉H₁₇F₂N₅O, 369.1; m/z found, 370.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.66-7.50 (m, 1H), 7.49-7.33(m, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 5.34-5.13 (m, 1H), 4.66-4.31 (m,1H), 4.29-4.01 (m, 1H), 3.52-3.33 (m, 1H), 3.25-3.11 (m, 1H), 2.75-2.54(m, 3H), 1.22-0.99 (m, 3H).

Example 94(R*)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 93 performedusing a CHIRALPAK AD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 2.78 min retention time). MS (ESI): mass calcd. forC₁₉H₁₇F₂N₅O, 369.1; m/z found, 369.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.76-7.65 (m, 1H), 7.48-7.36 (m, 1H), 7.04-6.81 (m, 3H), 5.63-5.41 (m,1H), 4.69-4.17 (m, 2H), 3.43-2.94 (m, 2H), 2.79-2.61 (m, 3H), 1.35-1.10(m, 3H).

Example 95(S*)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 93 performedusing a CHIRALPAK AD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.36 min retention time). MS (ESI): mass calcd. forC₁₉H₁₇F₂N₅O, 369.1; m/z found, 369.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.74-7.65 (m, 1H), 7.48-7.36 (m, 1H), 7.03-6.83 (m, 3H), 5.59-5.44 (m,1H), 4.67-4.19 (m, 2H), 3.43-3.23 (m, 1H), 3.14-2.96 (m, 1H), 2.78-2.63(m, 3H), 1.32-1.12 (m, 3H).

Example 96(4-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 87substituting 4-chlorobenzoic acid for 4-chloro-2-fluorobenzoic acid. MS(ESI): mass calcd. for C₁₉H₁₈ClN₅O, 367.1; m/z found, 368.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO) δ 7.88 (s, 1H), 7.58-7.49 (m, 5H), 6.97 (s, 1H),5.30-4.94 (m, 1H), 4.56-4.13 (m, 2H), 3.39-3.16 (m, 2H), 2.73-2.53 (m,3H), 1.10 (s, 3H).

Example 97(2-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 87substituting 2-chlorobenzoic acid for 4-chloro-2-fluorobenzoic acid. MS(ESI): mass calcd. for C₁₉H₁₈ClN₅O, 367.1; m/z found, 368.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO) δ 7.92-7.84 (m, 1H), 7.62-7.56 (m, 1H), 7.53-7.35(m, 3H), 7.01-6.92 (s, 1H), 5.35-5.16 (m, 1H), 4.51-4.27 (m, 1H),4.18-3.87 (m, 1H), 3.53-3.33 (m, 1H), 3.27-3.10 (m, 2H), 2.70-2.58 (s,2H), 1.24-0.99 (m, 3H).

Example 98(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 1-propanimidamide hydrochloride for acetamidinehydrochloride in the synthesis of Intermediate 34 and2-chloro-3-(trifluoromethyl)benzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₂₁H₁₉ClF₃N₅O, 449.1; m/zfound, 450.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.83-7.75 (m, 1H),7.75-7.67 (m, 1H), 7.57-7.41 (m, 2H), 6.93-6.82 (m, 1H), 5.68-5.52 (m,1H), 4.68-4.39 (m, 1H), 4.37-4.02 (m, 1H), 3.42-3.27 (m, 1H), 3.22-2.98(m, 2H), 2.96-2.83 (m, 1H), 1.47-1.10 (m, 6H).

Example 99(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 98 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.78 min retention time). MS (ESI): mass calcd. forC₂₁H₁₉ClF₃N₅O, 449.1; m/z found, 450.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 7.97 (d, J=8.0 Hz, 1H), 7.92-7.80 (m, 2H), 7.77-7.61 (m, 1H), 7.00 (s,1H), 5.39-5.19 (m, 1H), 4.56-4.29 (m, 1H), 4.18-3.89 (m, 1H), 3.58-3.33(m, 1H), 3.27-3.11 (m, 1H), 2.96-2.76 (m, 2H), 1.39-1.01 (m, 6H).

Example 100(S*)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 98 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (98% single enantiomer,4.53 min retention time). MS (ESI): mass calcd. for C₂₁H₁₉ClF₃N₅O,449.1; m/z found, 450.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.97 (d,J=7.9 Hz, 1H), 7.92-7.82 (m, 2H), 7.76-7.63 (m, 1H), 7.00 (s, 1H),5.37-5.18 (m, 1H), 4.57-4.29 (m, 1H), 4.20-3.88 (m, 1H), 3.57-3.35 (m,1H), 3.27-3.13 (m, 1H), 2.96-2.75 (m, 2H), 1.40-1.01 (m, 6H).

Example 101(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2-methylpropanimidamide hydrochloride for acetamidinehydrochloride in the synthesis of Intermediate 34 and2-chloro-3-(trifluoromethyl)benzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₂₂H₂₁ClF₃N₅O, 463.1; m/zfound, 464.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.83-7.74 (m, 1H),7.75-7.67 (m, 1H), 7.57-7.42 (m, 2H), 6.92-6.80 (m, 1H), 5.72-5.50 (m,1H), 4.71-4.38 (m, 1H), 4.37-4.03 (m, 1H), 3.42-3.16 (m, 1H), 3.16-2.91(m, 2H), 1.46-1.07 (m, 9H).

Example 102(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 101 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4 6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 3.38 min retention time). MS (ESI): mass calcd. forC₂₂H₂₁ClF₃N₅O, 463.1; m/z found, 464.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 7.97 (d, J=7.8 Hz, 1H), 7.87 (t, J=13.5 Hz, 2H), 7.77-7.63 (m, 1H),7.01 (s, 1H), 5.39-5.16 (m, 1H), 4.57-4.28 (m, 1H), 4.18-3.82 (m, 1H),3.59-3.35 (m, 1H), 3.25-2.96 (m, 2H), 1.40-0.99 (m, 9H).

Example 103(S*)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 101 performedusing a CHIRALCEL OD-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH. The enantiomeric purity was confirmed by analyticalSFC using a CHIRALCEL OD-H (250×4 6 mm) and a mobile phase of 75% CO₂,25% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (98% single enantiomer,3.93 min retention time). MS (ESI): mass calcd. for C₂₂H₂₁ClF₃N₅O,463.1; m/z found, 464.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.97 (d,J=7.9 Hz, 1H), 7.92-7.82 (m, 2H), 7.77-7.61 (m, 1H), 7.04-6.98 (m, 1H),5.38-5.18 (m, 1H), 4.60-4.27 (m, 1H), 4.18-3.86 (m, 1H), 3.60-3.33 (m,1H), 3.26-2.95 (m, 2H), 1.38-0.98 (m, 9H).

Example 104(2,4-dichloro-3-fluorophenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 1-propanimidamide hydrochloride for acetamidinehydrochloride in the synthesis of intermediate 34 and2,4-dichloro-3-fluorobenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI): mass calcd. for C₂₀H₁₈Cl₂FN₅O, 433.1; m/zfound, 434.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.75-7.65 (m, 1H),7.48-7.34 (m, 1H), 7.16-7.02 (m, 1H), 6.94-6.82 (m, 1H), 5.68-5.45 (m,1H), 4.72-4.25 (m, 1H), 4.19-4.01 (m, 1H), 3.45-3.24 (m, 1H), 3.22-2.82(m, 3H), 2.13-1.99 (m, 1H), 1.56-1.07 (m, 6H).

Example 105(4-(1H-pyrazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone

The title compound was prepared in a manner analogous to Example 22substituting 2,3-dimethylbenzoic acid for 2,3-dichlorobenzoic acid inExample 22, step c. MS (ESI) mass calcd. C₁₉H₁₉N₅O, 333.2; m/z found334.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ 8.90-8.74 (m, 1H), 8.66-8.60(m, 1H), 7.85-7.74 (m, 1H), 7.23-7.01 (m, 3H), 6.53-6.47 (m, 1H),5.23-4.95 (m, 1H), 4.53-4.44 (m, 1H), 4.22-3.92 (m, 1H), 3.59-3.44 (m,2H), 3.37-3.26 (m, 1H), 2.34-2.27 (m, 3H), 2.26-2.13 (m, 3H).

Example 106(4-(1H-1,2,3-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

To a suspension of NaH 60% dispersion in mineral oil (21 mg, 0.53 mmol)in DMF (3 mL) was added 1,2,3-triazole (28 L, 0.48 mmol). When gasevolution had ceased the mixture was cooled to 0° C. and Intermediate 4was added (191 mg, 0.40 mmol). The mixture was allowed to warm to rtovernight and was then diluted with H₂O and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Chromatography on SiO₂ eluting with EtOAc/hexaneafforded the desired compound (18 mg, 10%). MS (ESI) mass calcd.C₁₂H₁₂ClF₃NO, 408.1; m/z found 409.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ9.04-8.90 (m, 1H), 8.69-8.65 (m, 1H), 7.89-7.78 (m, 2H), 7.57-7.46 (m,2H), 5.34-4.98 (m, 1H), 4.67-4.48 (m, 1H), 4.23-4.06 (m, 1H), 3.64-3.35(m, 3H).

Example 1077-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 22substituting 1H-1,2,3-triazole for pyrazole in Example 22, step a. MS(ESI) mass calcd. C₁₆H₁₂Cl₂N₆O, 374.05; m/z found 375.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): δ 9.12-8.97 (m, 1H), 8.02-7.95 (m, 2H), 7.58-7.52 (m,1H), 7.36-7.23 (m, 6H), 5.23-5.04 (m, 1H), 4.67-4.49 (m, 1H), 4.13-4.08(m, 1H), 3.60-3.42 (m, 2H), 3.36-3.21 (m, 1H).

Example 1087-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Example 22substituting 1H-1,2,3-triazole for pyrazole in Example 22, step a and2-chloro-3-(trifluoromethyl)benzoic acid for 2,3-dichlorobenzoic acid.MS (ESI) mass calcd. C₁₇H₁₂ClF₃N₆O, 408.07; m/z found 409.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): δ 9.12-8.98 (m, 1H), 8.02-7.96 (m, 2H), 7.83-7.78(m, 1H), 7.58-7.47 (m, 2H), 5.27-5.03 (m, 1H), 4.66-4.48 (m, 1H),4.20-4.05 (m, 1H), 3.57-3.43 (m, 2H), 3.36-3.22 (m, 1H).

Example 109(4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

Example 109, Step a: tert-butyl4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of Intermediate 2 (1.5 g, 5.6 mmol) in ACN (5 mL) wasadded 1, 2, 4 triazole (0.657 mL, 11.1 mmol) in one portion followed byHunig's base (1.9 mL, 11.1 mmol). The mixture was stirred at 110° C.overnight. The solvents were removed in vacuo and chromatography on SiO₂eluting with EtOAc/hexane afforded the desired compound (579 mg, 34%).MS (ESI) mass calcd. C₁₄H₁₈N₆O₂, 302.1; m/z found 303.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): δ 9.04 (s, 1H), 7.98 (s, 2H), 4.81-4.75 (m, 2H),3.75-3.69 (m, 2H), 3.29-3.22 (m, 2H), 1.51 (s, 9H).

Example 109, Step b:4-(4H-1,2,4-triazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 109 step a (574 mg, 1.9 mmol) in DCM (9.5 mL)was added TFA (3.8 mL). After stirring 2 h the reaction was concentratedin vacuo. The residue was redissolved in DCM and treated with Dowex 550Aresin to neutralize the TFA salt. The resin was removed by filtrationand concentration afforded a yellow solid (347 mg, 90%). This materialwas used without further purification. MS (ESI) mass calcd. C₉H₁₀N₆,202.2; m/z found 203.1 [M+H]⁺.

Example 109, step c:(4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

To the product of Example 109 step b (48 mg, 0.24 mmol) in DCM (3 mL)was added Intermediate 45 (61 mg, 0.25 mmol) and TEA (40 μL, 0.29 mmol).The reaction was stirred at room temperature overnight. The solventswere removed in vacuo and chromatography on SiO₂ eluting withEtOAc/hexane afforded the desired compound (93 mg, 94%). MS (ESI) masscalcd. C₁₇H₁₂ClF₃N₆O, 408.1; m/z found 409.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.14-8.95 (m, 1H), 8.04-7.95 (m, 2H), 7.83-7.77 (m, 1H),7.60-7.46 (m, 2H), 5.29-5.01 (m, 1H), 4.68-4.47 (m, 1H), 4.21-4.04 (m,1H), 3.60-3.22 (m, 3H).

Example 110(4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

Example 110, Step a: tert-butyl4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate

To a solution of Intermediate 2 (1.5 g, 5.6 mmol) in ACN (5 mL) wasadded 1, 2, 4 triazole (0.657 mL, 11.1 mmol) in one portion followed byHunig's base (1.9 mL, 11.1 mmol). The mixture was stirred at 110° C.overnight. The solvents were removed in vacuo and chromatography on SiO₂eluting with EtOAc/hexane afforded the desired compound (855 mg, 50%).MS (ESI) mass calcd. C₁₄H₁₈N₆O₂, 302.1; m/z found 303.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): δ 8.96 (s, 1H), 8.66-8.61 (m, 1H), 7.87-7.84 (m, 1H),4.78 (s, 2H), 3.76-3.71 (m, 2H), 3.43-3.36 (m, 2H), 1.51 (s, 9H).

Example 110, Step b:4-(1H-1,2,4-triazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 110, step a (850 mg, 2.8 mmol) in DCM (14 mL)was added TFA (5 mL). After stirring 2 h, the reaction was concentratedin vacuo. Chromatography on SiO₂ eluting with 2 M NH₃ in MeOH/DCMafforded the desired product as a pale yellow solid (190 mg, 33%). Thismaterial was used without further purification. MS (ESI) mass calcd.C₉H₁₀N₆, 202.2; m/z found 203.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.92(s, 1H), 8.63 (d, J=1.2 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 4.23 (s, 2H),3.36 (t, J=5.7 Hz, 2H), 3.23 (t, J=5.9 Hz, 2H).

Example 110, step c:(4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone

To the product of Example 110, step b (43 mg, 0.21 mmol) in DCM (2 mL)was added Intermediate 45 (54 mg, 0.22 mmol) and TEA (35 L, 0.26 mmol).The reaction was stirred at room temperature overnight. The solventswere removed in vacuo and chromatography on SiO₂ eluting withEtOAc/hexane afforded the desired compound (70 mg, 80%). MS (ESI) masscalcd. C₁₇H₁₂ClF₃N₆O, 408.1; m/z found 409.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.06-8.88 (m, 1H), 8.71-8.64 (m, 1H), 7.90-7.76 (m, 2H),7.59-7.46 (m, 2H), 5.35-4.97 (m, 1H), 4.68-4.47 (m, 1H), 4.24-4.05 (m,1H), 3.63-3.35 (m, 3H).

Example 111(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone

Example 111, step a:4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the microwave vial was added the Intermediate 6 (262 mg, 0.99 mmol)and 1-(tetrahydropyran-2-yl)-1h-pyrazole-5-boronic acid pinacol ester(347 mg, 1.2 mmol) followed by dioxane (5 mL) and 2M Na₂CO₃ (1.2 mL). Tothis mixture was added Pd(Ph₃P)₄ (57 mg, 0.049 mmol) and the reactionheated in the microwave for 1 h at 150° C. The reaction was diluted withwater and extracted with DCM and EtOAc. The combined organic extractswere dried over Na₂SO₄, filtered and concentrated in vacuo.Chromatography on SiO₂ eluting with 2 M NH₃ in MeOH/DCM afforded thedesired product (255 mg, 90%). MS (ESI) mass calcd. C₁₅H₁₉N₅O, 285.2;m/z found 286.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 9.09-9.03 (m, 1H),7.70-7.63 (m, 1H), 6.56-6.50 (m, 1H), 5.84-5.75 (m, 1H), 4.27-4.00 (m,2H), 3.96-3.88 (m, 1H), 3.50-3.39 (m, 1H), 3.32-3.25 (m, 1H), 3.12-3.03(m, 1H), 2.99-2.90 (m, 1H), 2.86-2.77 (m, 1H), 2.53-2.42 (m, 1H),2.15-2.03 (m, 2H), 1.74-1.48 (m, 3H).

Example 111, step b:(2-fluoro-3-(trifluoromethyl)phenyl)(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 1substituting the product of Example 111 step a for Intermediate 1 and2-fluoro-3-(trifluoromethyl)benzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) mass calcd.C₂₃H₂₁F₄N₅O₂, 475.4; m/z found 476.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ9.19-9.03 (m, 1H), 7.77-7.63 (m, 3H), 7.41-7.35 (m, 1H), 6.59-6.48 (m,1H), 5.91-5.77 (m, 1H), 5.32-5.23 (m, 1H), 4.93-4.81 (m, 1H), 4.75-4.53(m, 1H), 3.93-3.86 (m, 1H), 3.71-3.62 (m, 1H), 3.52-3.40 (m, 1H),3.11-2.82 (m, 2H), 2.53-2.41 (m, 1H), 2.16-2.06 (m, 2H), 1.74-1.59 (m,2H), 1.57-1.49 (m, 1H).

Example 111, step c:(4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 33substituting the product of Example 111 step b for Intermediate 20. MS(ESI) mass calcd. C₁₈H₁₃F₄N₅O, 391.1; m/z found 392.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): δ 11.10 (s, 1H), 9.11-8.93 (m, 1H), 7.79-7.61 (m, 3H),7.43-7.32 (m, 1H), 7.00-6.91 (m, 1H), 5.06 (s, 1H), 4.72-3.57 (m, 3H),3.40-3.13 (m, 2H).

Example 112(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

Example 112, step a: ethyl 2-(benzylamino)propanoate

To a mixture of DL-alanine ethyl ester hydrochloride (913 mg, 5.9 mmol)in DCE (15 mL) was added TEA (1.2 mL, 8.8 mmol) followed by benzaldehyde(0.538 mL), 5.3 mmol) and Na(OAc)₃BH (2.0 g, 9.4 mmol). The mixture wasstirred at room temperature overnight and then quenched with saturatedaqueous NaHCO₃ solution. The layers were separated and the aqueous layerextracted with DCM. The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. Chromatography on SiO₂ eluting

EtOAc/hexane afforded the desired compound as a colorless liquid (798mg, 73%). MS (ESI) mass calcd. C₁₂H₁₇NO₂, 207.1; m/z found 208.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): δ7.39-7.23 (m, 5H), 4.23-4.16 (m, 2H),3.83-3.65 (m, 2H), 3.37 (q, J=7.0 Hz, 1H), 1.34-1.27 (m, 6H).

Example 112, step b: methyl4-(benzyl(1-ethoxy-1-oxopropan-2-yl)amino)butanoate

To a solution of the product of Example 112, step a (794 mg, 3.8 mmol)in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol)followed by Na(OAc)₃BH (1.6 g, 7.7 mmol). The mixture was stirred atroom temperature overnight and then quenched by the addition ofsaturated aqueous NaHCO₃ solution. The layers were separated and thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Chromatography on SiO₂ column eluting withEtOAc/hexane afforded the desired compound as a colorless liquid (1.11g, 95%). MS (ESI) mass calcd. C₁₇H₂₅NO₄, 307.2; m/z found 308.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H),3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m,2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H).

Example 112, step c: methyl1-benzyl-2-methyl-3-oxopiperidine-4-carboxylate and ethyl1-benzyl-2-methyl-3-oxopiperidine-4-carboxylate

To a solution of the product of Example 112, step b (1.11 g, 3.62 mmol)in toluene (74 mL) was added KOtBu (731 mg, 6.52 mmol). The mixture wasstirred at room temperature overnight and then quenched with saturatedaqueous NH₄Cl solution. The aqueous layer was extracted with DCM and thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo to 790 mg of crude material. Chromatography onSiO₂ eluting EtOAc/hexane afforded 576.7 mg of a mixture of methyl1-benzyl-2-methyl-3-oxopiperidine-4-carboxylate and ethyl1-benzyl-2-methyl-3-oxopiperidine-4-carboxylate in a ratio of 40:60 asdetermined by NMR analysis. This mixture was taken on to step d. MS(ESI) mass calcd. C₁₅H₁₉NO₃, 261.1; m/z found 262.2 [M+H]⁺ and MS (ESI)mass calcd. C₁₆H₂₁NO₃; 275.2 m/z found 276.2 [M+H]⁺.

Example 112, step d:7-benzyl-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

To a solution of the mixture of products from Example 112, step c, (575mg, 2.09 mmol) in EtOH (10 mL) was added formamidine hydrochloride (257mg, 3.13 mmol) followed by NaOEt (1.95 mL, 5.21 mmol) dropwise. Themixture was then heated to reflux overnight and the reaction was notcomplete as determined by LC/MS analysis. Additional formamidinehydrochloride (130 mg, 1.57 mmol) and NaOEt (1 mL) was added and heatingwas continued overnight. The reaction was treated with 1 N HCl until pH6 and concentrated in vacuo. The residue was then azeotroped withtoluene. Chromatography on SiO₂ eluting with IPA/EtOAc afforded thedesired compound as a pale yellow foam (391 mg, 73%). MS (ESI) masscalcd. C₁₅H₁₇N₃O, 255.1; m/z found 256.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 12.75 (s, 1H), 8.04 (s, 1H), 7.41-7.23 (m, 5H), 3.87-3.80 (m,1H), 3.74-3.63 (m, 2H), 3.01-2.91 (m, 1H), 2.74-2.58 (m, 2H), 2.56-2.46(m, 1H), 1.42 (d, J=6.8, 3H).

Example 112, step e:7-benzyl-4-chloro-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 8substituting the product of Example 112, step d for Intermediate 7. MS(ESI) mass calcd. C₁₅H₁₆ClN₃, 273.1; m/z found 274.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): δ 8.76 (s, 1H), 7.39-7.26 (m, 5H), 3.93-3.83 (m, 2H),3.72-3.66 (m, 1H), 3.07-3.00 (m, 1H), 2.88-2.79 (m, 1H), 2.77-2.69 (m,2H), 1.48 (d, J=6.8 Hz, 3H).

Example 112, step f:7-benzyl-8-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

The title compound was prepared in a manner analogous to Intermediate 19substituting the product of Example 112 step e for Intermediate 11. MS(ESI) mass calcd. C₂₃H₂₇N₅O, 389.2; m/z found 390.3 [M+H]⁺

Example 112, step g,8-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To the product of Example 112, step f (356 mg, 0.91 mmol) in EtOH (9 mL)was added a catalytic amount of 10% Pd/C Degussa type followed by aballoon of hydrogen gas. The mixture was stirred at room temperatureovernight. The balloon was refilled with hydrogen gas and an additionalspatula tip of 10% Pd/C was added. After an additional 24 h and thereaction was complete. The catalyst was removed by filtration and theliquid was concentrated in vacuo to afford the desired product (268 mg,98%). MS (ESI) mass calcd. C₁₆H₂₁N₅O, 299.2; m/z found 300.2 [M+H]⁺

Example 112, step h:(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting the product of Example 112 step g for Intermediate 43 andIntermediate 45 for Intermediate 44. MS (ESI) mass calcd. C₁₉H₁₅ClF₃N₅O,421.1; m/z found 422.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.17-8.94 (m,1H), 7.86-7.30 (m, 4H), 6.98-6.86 (m, 1H), 5.90-5.76 (m, 1H), 5.17-5.03(m, 0.5H), 4.67-4.47 (m, 0.5H), 3.68-2.92 (m, 3H), 1.84-1.49 (m, 3H).

Example 113(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 112 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 65% CO₂,35% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 1.73 minretention time). MS (ESI) mass calcd. C₁₉H₁₅ClF₃N₅O, 421.1; m/z found421.7 [M+H]⁺

Example 114(S*)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 112 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 65% CO₂,35% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 2.76 minretention time). MS (ESI) mass calcd. C₁₉H₁₅ClF₃N₅O, 421.1; m/z found421.7 [M+H]⁺

Example 115(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

To a solution of the product of Example 112, step g (60 mg, 0.20 mmol)in DCM (2 mL) was added 2-chloro-4-fluoro-3-(trifluoromethyl)benzoicacid (49 mg, 0.20 mmol), followed by EDCI (116 mg, 0.607 mmol), HOBt (19mg, 0.14 mmol) and TEA (2.0 mL, 0.607 mmol). The reaction was stirred atroom temperature overnight. The crude mixture was treated directly withTFA (0.8 mL) and triethylsilane (81 L, 0.20 mmol) and stirred for 3 h.The solvents were removed in vacuo and the residue was azeotroped withtoluene (1×). Chromatography on SiO₂ eluted with EtOAc/hexane affordedthe desired product (59 mg, 66%). MS (ESI) mass calcd. C₁₉H₁₄ClF₄N₅O,439.1; m/z found 440.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD): δ 9.08-8.87 (m,1H), 7.92-7.68 (m, 2H), 7.57-7.44 (m, 1H), 7.10-6.92 (m, 1H), 5.71-5.63(m, 1H), 3.68-3.33 (m, 3H), 3.19-3.08 (m, 1H), 1.77-1.56 (m, 3H).

Example 116(R*)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 115 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 70% CO₂,30% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 30% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 2.47 minretention time). MS (ESI) mass calcd. C₁₉H₁₄ClF₄N₅O, 439.1; m/z found440.0 [M+H]⁺

Example 117(S*)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 115 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 70% CO₂,30% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 30% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (98% single enantiomer, 4.09 minretention time). MS (ESI) mass calcd. C₁₉H₁₄ClF₄N₅O, 439.1; m/z found440.0 [M+H]⁺.

Example 118(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2,3-dichloro-4-fluorobenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44 and the product of Example 112, step g for Intermediate43. MS (ESI) mass calcd. C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found 406.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 9.04-8.89 (m, 1H), 7.79-7.70 (m, 1H),7.56-7.28 (m, 2H), 7.07-6.96 (m, 1H), 5.71-5.62 (m, 1H), 3.73-3.32 (m,3H), 3.29-3.07 (m, 1H), 1.78-1.54 (m, 3H).

Example 119(R*)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 118 performedusing CHIRALCEL OD-H (5 nm, 250×20 mm) and a mobile phase of 60% CO₂,40% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 2.10 minretention time). MS (ESI) mass calcd. C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found406.0 [M+H]⁺.

Example 120(S*)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 118 performedusing CHIRALCEL OD-H (5 nm, 250×20 mm) and a mobile phase of 60% CO₂,40% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 2.84 minretention time). MS (ESI) mass calcd. C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found406.0 [M+H]⁺

Example 121((2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 115substituting 2,4-dichloro-3-fluorobenzoyl chloride for2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid. MS (ESI) mass calcd.C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found 406.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD): δ9.05-8.88 (m, 1H), 7.80-7.43 (m, 2H), 7.40-7.21 (m, 1H), 7.08-6.93 (m,1H), 5.71-5.61 (m, 1H), 4.53-4.46 (m, OH), 3.70-3.33 (m, 3H), 3.28-3.06(m, 1H), 1.80-1.53 (m, 3H).

Example 122(R*)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 121 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 60% CO₂,40% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 2.08 minretention time). MS (ESI) mass calcd. C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found406.0 [M+H]⁺.

Example 123(S*)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 121 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 60% CO₂,40% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOHcontaining 0.3% iPrNH₂ over 7 minutes. (99% single enantiomer, 2.78 minretention time). MS (ESI) mass calcd. C₁₈H₁₄Cl₂FN₅O, 405.1; m/z found406.0 [M+H]⁺.

Example 124(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

1-bromo-2-fluoroethane (59 mL, 0.688 mmol), Cs₂CO₃ (560 mg, 1.72 mmol)and the product from Example 56 (250 mg, 0.574 mmol) were combined inDMF (2 mL) and heated at 120° C. for 10 min under microwave irradiation.The reaction mixture was treated with water and extracted with DCM. Theorganic layer was separated, dried (Na₂SO₄), filtered and concentratedin vacuo. The crude product was purified by chromatography (silica,EtOAc in Heptane 30/70 to 100/0), the desired fractions were collected,the solvent evaporated in vacuo. The racemic product (72 mg, 26%)obtained by trituration with DIPE. The title compound, absoluteconfiguration unknown, was obtained by chiral SFC purification of theracemic product using a CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobilephase of 80% CO₂, 20% EtOH. The enantiomeric purity was confirmed byanalytical SFC using a CHIRALCEL OD-H (250×4 6 mm) and a mobile phase of80% CO₂, 20% EtOH containing 0.3% iPrNH₂ over 7 minutes. (100% singleenantiomer, 5.15 min retention time). MS (ESI) mass calcd.C₂₂H₂₀ClF₄N₅O, 481.1; m/z found 482.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.81-7.73 (m, 1H), 7.70-7.40 (m, 3H), 7.06-7.02 (m, 1H), 5.70-5.51 (m,0.19H), 5.57-5.44 (m, 0.82H), 4.95-4.69 (m, 2H), 4.66-4.25 (m, 3.6H),4.07-3.97 (m, 0.42H), 3.46-3.28 (m, 1.6H), 3.25 (d, J=17.1 Hz, 0.19H),3.08 (dd, J=16.9, 5.8 Hz, 0.19H), 2.76 (s, 1.05H), 2.68 (s, 0.66H), 2.67(s, 1.29H), 1.28 (d, J=7.2 Hz, 1.05H), 1.26 (d, J=6.9 Hz, 0.72H), 1.25(d, J=6.9 Hz, 0.66H), 1.10 (d, J=6.7 Hz, 0.57H).

Example 125 (S*)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7-(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained bychiral SFC purification of the racemic product of Example 124 using aCHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 80% CO₂, 20%EtOH. The enantiomeric purity was confirmed by analytical SFC using aCHIRALCEL OD-H (250×4 6 mm) and a mobile phase of 80% CO₂, 20% EtOHcontaining 0.3% iPrNH₂ over 7 minutes. (99% single enantiomer, 5.85 minretention time). MS (ESI) mass calcd. C₂₂H₂₀ClF₄N₅O, 481.1; m/z found482.1 [M+H]⁺.

Example 126(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 124substituting 2-bromoethyl methyl ether for 1-bromo-2-fluoroethane. MS(ESI) mass calcd. C₂₃H₂₃ClF₃N₅O₂, 493.1; m/z found 494.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) δ 7.81-7.73 (m, 0.85H), 7.70-7.64 (m, 0.15H), 7.57 (d,J=2.3 Hz, 0.40H), 7.56-7.40 (m, 2.60H), 7.01 (d, J=2.3 Hz, 0.15H), 7.00(d, J=2.3 Hz, 0.45H), 6.99 (d, J=2.3 Hz, 0.40H), 5.60 (d, J=19.7 Hz,0.15H), 5.56-5.45 (m, 0.85H), 4.61 (d, J=18.5 Hz, 0.45H), 4.45-4.25 (m,3.35H), 4.06-3.98 (m, 0.45H), 3.86-3.70 (m, 2H), 3.53-3.21 (m, 4.50H),3.15-3.05 (m, 0.25H), 2.75 (s, 1.20H), 2.67 (s, 0.45H), 2.66 (s, 1.35H),1.23-1.30 (m, 2.55H), 1.10 (d, J=6.9 Hz, 0.45H).

Example 127(S*)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 126 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 80% CO₂,20% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 80% CO₂, 20% EtOHcontaining 0.3% iPrNH₂ over 7 minutes. (99% single enantiomer, 4.27 minretention time). MS (ESI) mass calcd. C₂₃H₂₃ClF₃N₅O₂, 493.1; m/z found494.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.73 (m, 1H), 7.59-7.40 (m,3H), 7.01 (d, J=2.3 Hz, 0.23H), 7.00 (d, J=2.5 Hz, 0.40H), 6.99 (d,J=2.3 Hz, 0.37H), 5.63-5.44 (m, 1H), 4.61 (d, J=18.5 Hz, 0.40H),4.46-4.24 (m, 3.24H), 4.07-3.97 (m, 0.40H), 3.87-3.70 (m, 2H), 3.51-3.21(m, 4.78H), 3.09 (dd, J=17.6, 5.5 Hz, 0.18H), 2.75 (s, 1.11H), 2.67 (s,0.69H), 2.66 (s, 1.20H), 1.30-1.22 (m, 2.31H), 1.09 (d, J=6.9 Hz,0.69H).

Example 128(R*)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 126 performedusing CHIRALCEL OD-H (5 μm, 250×20 mm) and a mobile phase of 80% CO₂,20% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 80% CO₂, 20% EtOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 3.49 minretention time). MS (ESI) mass calcd. C₂₃H₂₃ClF₃N₅O₂, 493.1; m/z found494.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.82-7.72 (m, 1H), 7.60-7.40 (m,3H), 7.01 (d, J=2.5 Hz, 0.23H), 7.00 (d, J=2.3 Hz, 0.40H), 6.99 (d,J=2.3 Hz, 0.37H), 5.65-5.44 (m, 1H), 4.61 (d, J=18.3 Hz, 0.40H),4.45-4.25 (m, 3.24H), 4.06-3.97 (m, 0.40H), 3.87-3.70 (m, 2H), 3.53-3.20(m, 4.78H), 3.09 (dd, J=16.9, 5.8 Hz, 0.18H), 2.75 (s, 1.11H), 2.67 (s,0.69H), 2.66 (s, 1.20H), 1.30-1.22 (m, 2.31H), 1.09 (d, J=6.9 Hz,0.69H).

Intermediate 46:2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Pd(dppf)₂Cl₂.HCl (102 mg, 0.14 mmol) was added to a degassed mixture of2-bromo-6-fluoropyridine (410 mg, 2.33 mmol), bis(pinacolato)diboron(828 mg, 3.26 mmol) and KOAc (685 mg, 6.99 mmol) in dioxane (6 mL) atroom temperature. The mixture was heated at 115° C. for 1 h. The solidmaterial was then filtered off the solvent evaporated and the crudecompound purified by chromatography (silica, MeOH in DCM 0:100 to10:90). The desired fractions were collected to obtain the titlecompound (400 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (td, J=8.1, 7.2Hz, 1H), 7.70 (ddd, J=6.9, 2.8, 0.9 Hz, 1H), 6.98 (ddd, J=8.1, 2.7, 0.9Hz, 1H), 1.38 (s, 12H),

Example 129(2,3-dichloro-4-fluorophenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 1substituting Intermediate 46 for phenylboronic acid in the synthesis ofIntermediate 1, Step c and 2,3-dichloro-4-fluorobenzoic acid for2-chloro-3-(trifluoromethyl)benzoic acid. MS (ESI) mass calcd.C₁₉H₁₂Cl₂F₂N₄O, 420.0; m/z found 421.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ9.14 (s, 0.55H), 9.03 (s, 0.45H), 8.16 (br d, J=7.2 Hz, 0.55H), 8.11 (brd, J=7.2 Hz, 0.45H), 8.03-7.95 (m, 1H), 7.31-7.16 (m, 2H), 7.08 (dd,J=8.1, 2.6 Hz, 0.45H), 7.04 (dd, J=8.1, 2.3 Hz, 0.55H), 5.20 (d, J=19.4Hz, 0.55H), 4.95 (d, J=19.4 Hz, 0.55H), 4.59 (d, J=17.9 Hz, 0.45H), 4.46(d, J=17.9 Hz, 0.45H), 4.17-4.08 (m, 0.55H), 4.05-3.95 (m, 0.45H),3.59-3.26 (m, 3H).

Example 130(2-chloro-3-(trifluoromethyl)phenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 1substituting Intermediate 46 for phenylboronic acid in the synthesis ofIntermediate 1, Step c. MS (ESI) mass calcd. C₂₀H₁₃ClF₄N₄O, 436.1; m/zfound 437.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.15 (s, 0.55H), 9.03 (s,0.45H), 8.16 (d, J=7.2 Hz, 0.55H), 8.11 (d, J=7.2 Hz, 0.45H), 8.05-7.93(m, 1H), 7.79 (br t, J=8.7, 8.7 Hz, 1H), 7.59-7.44 (m, 2H), 7.08 (dd,J=8.1, 2.3 Hz, 0.45H), 7.04 (dd, J=8.1, 2.3 Hz, 0.55H), 5.27 (d, J=19.7Hz, 0.55H), 4.93 (d, J=19.7 Hz, 0.55H), 4.60 (d, J=18.2 Hz, 0.45H), 4.46(d, J=18.2 Hz, 0.45H), 4.23-4.15 (m, 0.45H), 4.02-3.94 (m, 0.45H),3.60-3.28 (m, 3.1H).

Intermediate 47:2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Intermediate 47, Step A: tert-butyl2,6-dimethyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate 19substituting Intermediate 36 for Intermediate 11. MS (ESI): mass calcd.for C₂₂H₃₁N₅O₃ 413.2; m/z found, 414.3 [M+H]⁺.

Intermediate 47, Step B:2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

TFA (1.2 mL) was added to a solution of the product of Intermediate 47,step A (250 mg, 0.605 mmol) and triethylsilane (0.240 mL, 1.51 mmol) inDCM (5 mL). The reaction was stirred for 3 hours at room temperature.The mixture was quenched with sat. NaHCO3 and the aqueous layer wasextracted with DCM (3×). The combined organic extracts were dried overMgSO4, filtered and concentrated. The crude material was purified byPrep Agilent system with a XBridge C18 OBD 30×100 mm column eluting with5 to 99% (0.05% NH₄OH in H₂O)/ACN over 17 min (138 mg, 99%). MS (ESI)mass calcd. C₁₂H₁₅N₅, 229.1; m/z found 230.1 [M+H]⁺

Intermediate 48: 2,4-dimethylbenzoyl chloride

The title compound was prepared in a manner analogous to Intermediate 44substituting 2,4-dimethylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid. The product was used as iswithout additional purification.

Intermediate 49: 2,3-dimethylbenzoyl chloride

The title compound was prepared in a manner analogous to Intermediate 44substituting 2,3-dimethylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid. The product was used as iswithout additional purification.

Example 131(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,4-dimethylphenyl)methanone

Intermediate 48 (115 mg, 0.686 mmol) was added to a solution ofIntermediate 47 (157 mg, 0.686 mmol) and DIEA (0.355 mL, 2.05 mmol) inDCM (2 mL). The reaction was stirred at room temperature for one hour.The solvents were removed in vacuo and the crude mixture was purified bychromatography on a Prep Agilent system with a XBridge C18 OBD 30×100 mmcolumn eluting with 5 to 99% (0.05% NH₄OH in H₂O)/ACN over 17 min toafford the desired product (10 mg, 4%). MS (ESI) mass calcd. C₂₁H₂₃N₅O,361.2; m/z found 362.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.28 (br s,1H), 7.78-7.60 (m, 1H), 7.18-6.70 (m, 4H), 5.75-5.44 (m, 1H), 4.59-4.08(m, 2H), 3.44-2.86 (m, 2H), 2.83-2.54 (m, 3H), 2.46-2.03 (m, 6H),1.38-0.97 (m, 3H).

Example 132(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone

The title compound was prepared in a manner analogous to Example 131substituting Intermediate 49 for Intermediate 48. MS (ESI) mass calcd.C₂₁H₂₃N₅O, 361.2; m/z found 362.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ11.12 (br s, 1H), 7.84-7.61 (m, 1H), 7.24-6.76 (m, 4H), 5.78-5.50 (m,1H), 4.56-4.12 (m, 2H), 3.39-2.83 (m, 2H), 2.83-2.60 (m, 3H), 2.42-2.02(m, 6H), 1.31-1.09 (m, 3H).

Example 133(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(4-fluoro-2-methylphenyl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 4-fluoro-2-methylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI) mass calcd. C₂₀H₂₀FN₅O, 365.2; m/z found 366.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.18 (br s, 1H), 7.81-7.61 (m, 1H),7.24-7.08 (m, 1H), 7.05-6.77 (m, 3H), 5.73-5.49 (m, 1H), 4.56-4.08 (m,2H), 3.46-2.86 (m, 2H), 2.81-2.58 (m, 3H), 2.49-2.08 (m, 3H), 1.42-1.02(m, 3H).

Example 134(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-fluoro-2-methylphenyl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 3-fluoro-2-methylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI) mass calcd. C₂₀H₂₀FN₅O, 365.2; m/z found366.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 6 (br s, 1H), 7.77-7.63 (m, 1H),7.25-6.79 (m, 4H), 5.72-5.47 (m, 1H), 4.57-3.96 (m, 2H), 3.41-2.87 (m,2H), 2.83-2.58 (m, 3H), 2.39-1.94 (m, 3H), 1.36-1.05 (m, 3H).

Example 135(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-methylphenyl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 2-fluoro-3-methylbenzoic acid for2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis ofIntermediate 44. MS (ESI) mass calcd. C₂₀H₂₀FN₅O, 365.2; m/z found 366.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.3-11.0 (br s., 1H), 7.84-7.54 (m,1H), 7.38-7.00 (m, 3H), 6.95-6.67 (m, 1H), 5.77-5.33 (m, 1H), 4.86-4.10(m, 2H), 3.45-2.91 (m, 2H), 2.85-2.52 (m, 3H), 2.50-2.07 (m, 3H),1.47-0.95 (m, 3H).

The following examples (P136-P138) are prophetic examples:

Example P136(R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

Example P137(R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(phenyl)methanone

Example P138(2,4-dichlorophenyl)((6R,8S)-2,6,8-trimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

Example 139(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone

The title compound was prepared in a manner analogous to Example 87substituting -fluoro-3-(trifluoromethoxy)benzoic acid for4-chloro-2-fluorobenzoic acid. MS (ESI) mass calcd. C₂₀H₁₇F₄N₅O₂,435.13; m/z found 435.90 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.41-10.89(m, 1H), 7.81-7.63 (m, 1H), 7.57-7.16 (m, 3H), 6.96-6.81 (m, 1H),5.82-5.38 (m, 1H), 4.75-4.00 (m, 2H), 3.49-2.95 (m, 2H), 2.86-2.55 (m,3H), 1.45-0.98 (m, 3H).

Example 140(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 3-(trifluoromethoxy)benzoic acid for2-methyl-3(trifluoromethyl)benzoic acid in the synthesis of Intermediate44. Purification of the title compound was accomplished usingchromatography on SiO₂ eluting with EtOAc/hexanes followed bytrituration in hot acetonitrile (55° C.) for 2 minutes and thentrituration in acetonitrile at room temperature. After 2 hours, theprecipitates were collected and washed with Et₂O to afford desiredmaterial. MS (ESI): mass calcd. for C₂₀H₁₈F₃N₅O₂, 417.14; m/z found,417.95 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 11.69-11.02 (m, 1H), 7.75-7.65(m, 1H), 7.53-7.46 (m, 1H), 7.40-7.36 (m, 1H), 7.35-7.30 (m, 2H),6.98-6.76 (m, 1H), 5.67-5.25 (m, 1H), 4.87-4.25 (m, 2H), 3.43-2.90 (m,2H), 2.71 (s, 3H), 1.24 (s, 3H).

Example 141(R*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 140 performedusing a CHIRALCEL OJ-H (5 μm, 250×20 mm) column and a mobile phase of90% CO₂, 10% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALCEL OJ-H (250×4 6 mm) and amobile phase of 90% CO₂, 10% iPrOH containing 0.3% iPrNH₂ over 15minutes. (100% single enantiomer, 7.78 min retention time). MS (ESI):mass calcd. C₂₀H₁₈F₃N₅O₂, 417.14; m/z found, 417.95 [M+H]⁺. ¹H NMR (500MHz, CDCl3) δ 11.47-10.68 (m, 1H) 7.71 (d, J=2.2 Hz, 1H), 7.54-7.45 (m,1H), 7.41-7.35 (m, 1H), 7.34-7.29 (m, 2H), 6.87 (d, J=2.1 Hz, 1H),5.65-5.39 (m, 1H), 4.75-4.22 (m, 2H), 3.41-3.18 (m, 1H), 3.11-2.98 (m,1H), 2.71 (s, 3H), 1.35-1.16 (m, 3H).

Example 142(S*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 140 performedusing a CHIRALCEL OJ-H (5 μm, 250×20 mm) column and a mobile phase of90% CO₂, 10% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALCEL OJ-H (250×4 6 mm) and amobile phase of 90% CO₂, 10% iPrOH containing 0.3% iPrNH₂ over 15minutes. (98.2% single enantiomer, 9.29 min retention time). MS (ESI):mass calcd. C₂₀H₁₈F₃N₅O₂, 417.14; m/z found, 417.90 [M+H]⁺. ¹H NMR (500MHz, CDCl3) δ 11.47-10.68 (m, 1H) 7.71 (d, J=2.2 Hz, 1H), 7.54-7.45 (m,1H), 7.41-7.35 (m, 1H), 7.34-7.29 (m, 2H), 6.87 (d, J=2.1 Hz, 1H),5.65-5.39 (m, 1H), 4.75-4.22 (m, 2H), 3.41-3.18 (m, 1H), 3.11-2.98 (m,1H), 2.71 (s, 3H), 1.35-1.16 (m, 3H).

Example 143(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound was prepared in a manner analogous to Example 742-chloro-3-fluorobenzoic acid for substituting2-methyl-3(trifluoromethyl)benzoic acid in the synthesis of Intermediate44. Purification of title compound was done by chromatography on SiO₂eluting with EtOAc/hexanes. MS (ESI): mass calcd. for C₁₉H₁₇Cl F N₅O,385.11; m/z found, 386.10 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 11.36-10.95(m, 1H), 7.79-7.57 (m, 1H), 7.40-7.05 (m, 3H), 6.94-6.81 (m, 1H),5.73-5.46 (m, 1H), 4.74-4.03 (m, 2H), 3.45-2.89 (m, 2H), 2.82-2.58 (m,3H), 1.36-1.07 (m, 3H).

Example 144(R*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example C performedusing a CHIRALCEL OJ-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALCEL OJ-H (250×4 6 mm) and amobile phase of 75% CO₂, 25% iPrOH containing 0.3% iPrNH₂ over 7minutes. (100% single enantiomer, 3.38 min retention time). MS (ESI):mass calcd. C₁₉H₁₇Cl F N₅O, 385.11; m/z found, 386.10 [M+H]⁺. ¹H NMR(400 MHz, CDCl3) δ 11.60-10.80 (m, 1H), 7.79-7.57 (m, 1H), 7.40-7.05 (m,3H), 6.94-6.81 (m, 1H), 5.73-5.46 (m, 1H), 4.74-4.03 (m, 2H), 3.45-2.91(m, 2H), 2.82-2.58 (m, 3H), 1.36-1.07 (m, 3H).

Example 145(S*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example C performedusing a CHIRALCEL OJ-H (5 μm, 250×20 mm) column and a mobile phase of75% CO₂, 25% iPrOH containing 0.3% iPrNH₂. The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALCEL OJ-H (250×4 6 mm) and amobile phase of 75% CO₂, 25% iPrOH containing 0.3% iPrNH₂ over 7minutes. (100% single enantiomer, 5.23 min retention time). MS (ESI):mass calcd. C₁₉H₁₂Cl F N₅O, 385.11; m/z found, 386.10 [M+H]⁺. ¹H NMR(400 MHz, CDCl3) δ 11.35-10.86 (m, 1H), 7.79-7.57 (m, 1H), 7.40-7.05 (m,3H), 6.94-6.81 (m, 1H), 5.73-5.46 (m, 1H), 4.74-4.03 (m, 2H), 3.45-2.91(m, 2H), 2.82-2.58 (m, 3H), 1.36-1.07 (m, 3H).

Example 146(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-methoxy-2-methylphenyl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 3-methoxy-2-methylbenzoic acid for2-methyl-3(trifluoromethyl)benzoic acid in the synthesis of Intermediate44. MS (ESI): mass calcd. for C₂₁H₂₃N₅O₂, 377.19; m/z found, 378.20[M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 11.85-10.83 (m, 1H), 7.76-7.66 (m,1H), 7.26-7.14 (m, 1H), 6.93-6.70 (m, 3H), 5.69-5.53 (m, 1H), 4.49-4.13(m, 2H), 3.90-3.77 (m, 3H), 3.36-2.81 (m, 2H), 2.79-2.60 (m, 3H),2.27-1.94 (m, 3H), 1.31-1.07 (m, 3H).

Example 147(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(5-methoxypyridin-3-yl)methanone

The title compound was prepared in a manner analogous to Example 74substituting 5-methoxynicotinic acid hydrochloride for2-methyl-3(trifluoromethyl)benzoic acid in the synthesis of Intermediate44. MS (ESI): mass calcd. for C₁₉H₂₀N₆O₂, 364.16; m/z found, 365.20[M+H]⁺.

Pharmacological Examples

The in vitro affinity of the compounds of the invention for the rat andhuman P2X7 receptor was determined using a human peripheral bloodmononuclear cells (PBMCs), a human whole blood assay, a Ca²⁺ flux andradioligand binding assay in recombinant human P2X7 cells andrecombinant rat P2X7 cells. In Tables 2 and 3, when the data cell hasbeen left blank, it is intended to mean that the compound was not testedin that assay. The data represented in Tables 2 and 3 may represent avalue from a single determination or when the experiment was run morethan once, the data represent averages from between 2-12 runs.

P2X7 Antagonism in Human Peripheral Blood Mononuclear Cells (PBMCs) andHuman Whole Blood.

Human blood was collected using a blood donor program. PBMCs wereisolated from blood using a Ficoll density gradient technique. Briefly,blood was laid on Ficoll solution and centrifuged at RT for 20 minutesat 2000 rpm. The buffy layer (between red blood cells and plasma) wascarefully collected by aspiration, washed with PBS and centrifuged againat 1500 rpm for 15 minutes. The resulting cell pellet was washed andplated on 96 well-plates for experiments. For the Human Whole Bloodexperiments, 150 μl of human blood was platted on 96 well-plates.Lipopolysaccharide (LPS) (30 ng/ml) was added to each well and incubatedfor 1 hour. Test compounds were then added and incubated for 30 minutes.The P2X7 agonist, 2′(3′)-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate(Bz-ATP) was then added at a final concentration of 0.5 mM (PBMC) or 1mM (blood). Cells were incubated for an additional 1.5 hours. At thatpoint, supernatant was collected and stored for IL-1β assay usingmanufacturer's protocol for enzyme-linked immunosorbent assay (ELISA).Data was expressed as percent control, where control is defined as thedifference in IL-1β release in LPS+Bz-ATP samples and LPS only samples.Data was plotted as response (% control) versus concentration togenerate IC₅₀ values. In Tables 2 and 3, this data is represented byPBMC 1 μM (% control) and PBMC 10 μM (% control) and human whole bloodIC₅₀ (μM). Data are analyzed and graphed on Graphpad Prism 5. Foranalysis, each concentration point is averaged from triplicate valuesand the averaged values are plotted on Graphpad Prism. The IC₅₀ for eachcompound is then uploaded into 3DX.

P2X7 Antagonism in Recombinant Human P2X7 Cells or Recombinant Rat P2X7Cells: (a) Ca²⁺ Flux and (b) Radioligand Binding

(a) Ca²⁺ flux: 1321N1 cells expressing the recombinant human or rat P2X7channel was cultured in HyQ DME/(HyClone/Dulbecco's Modified EagleMedium) high glucose supplemented with 10% Fetal Bovine Serum (FBS) andappropriate selection marker. Cells were seeded at a density of 25000cells/well (96-well clear bottom black walled plates) in 100 μlvolume/well. On the day of the experiment, cell plates were washed withassay buffer, containing (in mM): 130 NaCl, 2 KCl, 1 CaCl₂, 1 MgCl₂, 10HEPES, 5 glucose; pH 7.40 and 300 mOs. After the wash, cells were loadedwith the Calcium-4 dye (Molecular Device) and incubated in the dark for60 minutes. Test compounds were prepared at 250× the test concentrationin neat DMSO. Intermediate 96-well compound plates were prepared bytransferring 1.2 μL of the compound into 300 μL of assay buffer. Afurther 3× dilution occurred when transferring 50 μL/well of thecompound plate to 100 μL/well in the cell plate. Cells were incubatedwith test compounds and dye for 30 minutes. Calcium dye fluorescence wasmonitored in FLIPR as the cells were challenged by adding 50 μL/well ofBzATP (final concentration is 250 μM BzATP (human and rat)). Thefluorescence change was measured 180 seconds after adding the agonist.Peak fluorescence was plotted as a function of BzATP concentration usingOrigin 7 software and the resultant IC₅₀ is shown in Tables 2 and 3under the column headings FLIPR (human) IC₅₀ (μM) and FLIPR (rat) IC₅₀(μM).

(b) Radioligand binding: human or rat P2X7-1321 N1 cells were collectedand frozen @ −80° C. On the day of the experiment, cell membranepreparations were made according to standard published methods. Thetotal assay volume was 100 μl:10 μl compound (10×)+(b) 40 μl tracer(2.5×)+50 μl membrane (2×). The tracer used for the assay was tritiatedA-804598. The compound can be prepared as described in the literature.(Donnelly-Roberts, D. Neuropharmacology 2008, 56 (1), 223-229.)Compounds, tracer and membranes were incubated for 1 hour @ 4° C. Theassay was terminated by filtration (GF/B filters pre-soaked with 0.3%PEI) and washed with washing buffer (Tris-HCl 50 mM). The IC₅₀ generatedin the binding assay was corrected for tracer concentration and affinityof the tracer to derive at the affinity (K) of the test compounds. Thedata are presented in Tables 2 and 3 under the headings: P2X7 humanK_(i) (μM) and P2X7 rat K_(i) (μM). Data are analyzed and graphed onGraphpad Prism 5. For analysis, each concentration point is averagedfrom triplicate values and the averaged values are plotted on GraphpadPrism.

TABLE 2 P2X7 activity of the compounds of Formula (I) and selectedcompounds in a panel of in-vitro assays Human PBMC PBMC P2X7 P2X7 FLIPRFLIPR whole 1 μm 10 μM human rat (human) (rat) blood Example (% (% K_(i)K_(i) IC₅₀ IC₅₀ IC₅₀ # control) control) (μM) (μM) (μM) (μM) (μM) 1 6.60.2239 0.0299 1.2706 2 19.4 0.0955 0.2512 0.0365 3.2359 3 2.5 0.79804.2462 4 50.2 0.3882 12.4738 5 72.0 12.7644 >10 6 100.0 49.5 7 14.20.0154 0.0145 0.0207 0.4894 0.56 8 27.5 0.2438 >10 9 96.3 9.8 10 21.50.0309 0.0219 0.0461 1.0116 2.00 11 45.8 0.0372 0.0617 0.4159 >10 1226.9 0.0589 0.0575 0.0281 5.9704 2.00 13 86.7 13.4 14 9.8 0.0631 0.03160.0251 3.1623 15 30.0 0.0794 0.0501 0.0316 6.3096 16 96.6 20.413.1826 >10 17 101.1 9.9 18 −0.5 0.0200 0.0050 0.0103 0.0762 19 13.80.0251 0.0261 0.0099 0.63 20 −0.2 0.0251 0.0035 0.0059 0.3381 1.23 21−15.5 0.0398 0.2799 3.2137 22 15.5 0.1977 28.0543 23 71.8 0.0095 0.02400.0045 2.4831 1.12 24 70.3 0.0266 0.0079 0.0119 0.0679 25 99.7 10.8 2691.0 16.1 27 48.8 0.4266 0.1170 4.5499 28 98.8 12.4 0.4519 8.5704 2963.6 0.7962 1.9679 30 80.8 21.0 31 95.4 9.2 32 66.5 0.2652 4.0504 3318.5 0.0164 0.0120 0.0080 1.1066 1.12 34 7.9 0.0631 0.0200 0.0861 2.016035 36.3 0.0398 0.0126 0.0483 0.2692 36 58.8 0.0794 0.0316 37 22.0 0.05010.0251 0.0121 0.6486 38 47.8 0.0776 0.0457 0.0634 1.3772 39 15.1 0.05010.0178 0.1000 0.0251 40 81.0 12.9 41 52.2 42 34.4 0.0794 0.0200 2.511943 36.2 0.0501 0.0100 0.0158 0.1585 44 44.6 0.0631 0.0348 0.1560 45 80.37.1 46 104.3 100.0 47 56.7 0.0398 0.0158 0.0079 >10 48 92.4 1.99535.0119 10.0000 49 84.9 16.3 50 100.4 83.5 51 87.5 17.3 52 76.9 9.3 5352.9 0.0631 0.0834 1.8880 54 5.0 0.1000 0.0210 0.5559 55 −2.1 0.01780.0459 0.1172 56 10.2 0.0372 0.0143 0.0124 57 −9.6 0.0631 0.0165 0.161158 5.0 0.0158 0.0028 0.0111 0.0103 0.16 59 2.8 1.7458 0.8610 60 10.80.0794 0.0655 0.2679 61 −1.2 0.4477 3.1117 62 44.7 0.0251 0.0078 0.005663 −4.1 0.0224 0.3162 0.0025 64 −2.1 0.0794 0.0164 0.0133 65 3.9 2.81841.2246 66 −6.1 0.0501 0.0100 0.0100 67 −1.3 0.0126 0.0135 0.0145 68 −0.50.0158 0.0127 0.0088 69 −6.2 1.7865 0.9376 70 −2.7 0.0398 0.0187 0.012471 −4.1 0.0126 0.0029 0.0024 72 −2.6 1.4521 1.1803 73 2.2 0.1259 0.09660.0178 74 22.5 0.0251 0.0100 0.0100 75 2.4 0.0063 0.0127 0.0077 76 14.30.4064 0.1262 77 20.9 0.0316 0.0631 0.0200 78 1.4 0.0079 0.0136 0.012979 2.6 3.2359 0.9886 80 18.4 0.0251 0.0251 0.0200 81 21.0 0.0079 0.01050.0153 82 −1.0 1.3152 0.8670 83 2.7 0.0316 0.0017 0.0149 84 7.5 0.01000.0019 0.0110 0.0131 85 −0.8 0.4571 0.8204 0.5861 86 92.2 87 0.4 0.03160.0336 0.0152 88 49.4 11.0408 8.7700 89 −16.4 0.0115 0.0010 0.01720.0159 90 91 −8.8 0.0251 0.0587 0.1318 92 9.4 1.5922 5.9566 93 −1.70.1995 0.0285 0.3846 94 71.8 >10 >10 95 −19.2 0.0316 0.0647 0.1014 963.8 0.6310 0.0500 1.8450 97 −3.1 0.1995 0.1663 13.9959 98 13.2 0.05500.0255 0.0149 99 16.4 0.0174 0.0139 0.0126 100 4.0 1.1940 0.2056 10113.6 0.1000 0.0824 0.0230 102 11.7 0.0200 0.0273 0.0130 103 6.3 1.03280.4140 104 −1.3 0.0398 0.0191 0.0237 105 94.4 106 100.4 107 71.8 0.00950.0240 0.0045 2.4831 1.12 108 70.3 0.0266 0.0079 0.0119 0.0679 109 2.20.0126 0.0121 0.4853 110 20.1 >10 >10 111 0.6 0.0501 0.3532 0.8072 112−1.8 0.0251 0.0129 0.0160 113 −2.1 0.0079 0.0028 0.0091 114 −0.5 0.63100.1337 0.1660 115 −3.1 0.0316 0.0139 0.0142 116 −4.4 0.0316 0.00590.0086 117 0.1 0.9683 1.2274 118 −0.6 0.0126 0.0057 0.0210 119 −1.50.0126 0.0100 0.0284 120 2.9 0.6561 1.5101 121 0.7 0.0200 0.0106 0.1279122 4.1 0.0200 0.0058 0.1279 123 13.3 0.5012 0.1524 1.0046 124 18.60.0251 0.0035 0.0310 0.0129 125 64.7 126 127 38.2 >10 >10 128 7.3 0.03160.0030 0.0296 0.0097 129 2.5 0.0398 0.1062 1.0641 130 12.9 0.0631 0.01741.0940 131 7.3 11.4025 >10 132 −0.1 0.5321 7.1614 133 0.1 0.9183 2.2182134 0.4 0.3311 1.2735 135 −1.0 0.4920 1.8707

The following compounds were tested in additional runs for the assaysdescribed above and the data is provided in Table 3.

TABLE 3 P2X7 activity of the compounds of Formula (I) and selectedcompounds in a panel of in-vitro assays Human PBMC PBMC P2X7 P2X7 FLIPRFLIPR whole 1 μM 10 μM human rat (human) (rat) blood Example (% (% K_(i)K_(i) IC₅₀ IC₅₀ IC₅₀ # control) control) (μM) (μM) (μM) (μM) (μM) 1 6.60.2239 0.0299 1.2706 2 19.4 0.0955 0.2512 0.0365 3.2359 3 2.5 0.79804.2462 4 50.2 0.3882 12.4738 5 72.0 12.7644 >10 6 100.0 49.5 7 14.20.0154 0.0145 0.0207 0.4894 0.562 8 27.5 0.2438 >10 9 96.3 9.8 10 21.50.0309 0.0219 0.0461 1.0116 1.995 11 45.8 0.0372 0.0617 0.4159 >10 1226.9 0.0589 0.0575 0.0281 5.9704 1.995 13 86.7 13.4 14 9.8 0.0631 0.03160.0251 3.1623 15 30.0 0.0794 0.0501 0.0316 6.3096 16 96.6 20.413.1826 >10 17 101.1 9.9 18 −0.5 0.0200 0.0050 0.0103 0.0762 19 13.80.0251 0.0261 0.0099 0.631 20 −0.2 0.0251 0.0035 0.0059 0.3381 1.230 21−15.5 0.0398 0.2799 3.2137 22 15.5 0.1977 28.0543 23 71.8 0.0095 0.02400.0045 2.4831 1.122 24 70.3 0.0266 0.0079 0.0119 0.0679 25 99.7 10.8 2691.0 16.1 27 48.8 0.4266 0.1170 4.5499 28 98.8 12.4 0.4519 8.5704 2963.6 0.7962 1.9679 30 80.8 21.0 31 95.4 9.2 32 66.5 0.2652 4.0504 3318.5 0.0164 0.0120 0.0080 1.1066 1.122 34 7.9 0.0631 0.0200 0.08612.0160 35 36.3 0.0398 0.0126 0.0483 0.2692 36 58.8 0.0794 0.0316 37 22.00.0501 0.0251 0.0121 0.6486 38 47.8 0.0776 0.0457 0.0634 1.3772 39 15.10.0501 0.0178 0.1000 0.0251 40 81.0 12.9 41 52.2 42 34.4 0.0794 0.02002.5119 43 36.2 0.0501 0.0100 0.0158 0.1585 44 44.6 0.0631 0.0348 0.156045 80.3 7.1 46 104.3 100.0 47 56.7 0.0398 0.0158 0.0079 >10 48 92.41.9953 5.0119 10.0000 49 84.9 16.3 50 100.4 83.5 51 87.5 17.3 52 76.99.3 53 52.9 0.0631 0.0834 1.8880 54 5.0 0.1000 0.0210 0.5559 55 −2.10.0178 0.0459 0.1172 56 10.2 0.0372 0.0143 0.0124 57 −9.6 0.0631 0.01650.1611 58 5.0 0.0158 0.0028 0.0111 0.0103 0.158 59 2.8 1.7458 0.8610 6010.8 0.0794 0.0655 0.2679 61 −1.2 0.4477 3.1117 62 44.7 0.0251 0.00780.0056 63 −4.1 0.0224 0.3162 0.0025 64 −2.1 0.0794 0.0164 0.0133 65 3.92.8184 1.2246 66 −6.1 0.0501 0.0100 0.0100 67 −1.3 0.0126 0.0135 0.014568 −0.5 0.0158 0.0127 0.0088 69 −6.2 1.7865 0.9376 70 −2.7 0.0398 0.01870.0124 71 −4.1 0.0126 0.0029 0.0024 72 −2.6 1.4521 1.1803 73 2.2 0.12590.0966 0.0178 74 22.5 0.0251 0.0100 0.0100 75 2.4 0.0063 0.0127 0.007776 14.3 0.4064 0.1262 77 20.9 0.0316 0.0631 0.0200 78 1.4 0.0079 0.01360.0129 79 2.6 3.2359 0.9886 80 18.4 0.0251 0.0251 0.0200 81 21.0 0.00790.0105 0.0153 82 −1.0 1.3152 0.8670 83 2.7 0.0316 0.0017 0.0149 84 7.50.0100 0.0019 0.0110 0.0131 85 −0.8 0.4571 0.8204 0.5861 86 92.2 87 0.40.0316 0.0336 0.0152 88 49.4 11.0408 8.7700 89 −16.4 0.0077 0.00120.0172 0.0159 90 91 −8.8 0.0251 0.0587 0.1318 92 9.4 1.5922 5.9566 93−1.7 0.1995 0.0285 0.3846 94 71.8 >10 >10 95 −19.2 0.0316 0.0647 0.101496 3.8 0.6310 0.0500 1.8450 97 −3.1 0.1995 0.1663 13.9959 98 13.2 0.05500.0255 0.0149 99 16.4 0.0174 0.0139 0.0126 100 4.0 1.1940 0.2056 10113.6 0.1000 0.0824 0.0230 102 11.7 0.0200 0.0273 0.0130 103 6.3 1.03280.4140 104 −1.3 0.0398 0.0191 0.0237 105 94.4 106 100.4 107 71.8 0.00950.0240 0.0045 2.4831 1.122 108 70.3 0.0266 0.0079 0.0119 0.0679 109 2.20.0126 0.0121 0.4853 110 20.1 >10 >10 111 0.6 0.0501 0.3532 0.8072 112−1.8 0.0251 0.0129 0.0160 113 −2.1 0.0079 0.0028 0.0091 114 −0.5 0.63100.1337 0.1660 115 −3.1 0.0316 0.0139 0.0142 116 −4.4 0.0316 0.00590.0086 117 0.1 0.9683 1.2274 118 −0.6 0.0126 0.0057 0.0210 119 −1.50.0126 0.0100 0.0284 120 2.9 0.6561 1.5101 121 0.7 0.0200 0.0106 0.1279122 4.1 0.0200 0.0058 0.1279 123 13.3 0.5012 0.1524 1.0046 124 18.60.0251 0.0035 0.0310 0.0129 125 64.7 126 127 38.2 >10 >10 128 7.3 0.03160.0030 0.0296 0.0097 129 2.5 0.0398 0.1062 1.0641 130 12.9 0.0631 0.01741.0940 131 7.3 11.4025 >10 132 −0.1 0.5321 7.1614 133 0.1 0.9183 2.2182134 0.4 0.3311 1.2735 135 −1.0 0.4920 1.8707 139 2.0 1.1561 1.4555 14052.5 >10 47.3151 141 −0.6 8.9950 12.3595 142 73.9 143 11.9 0.1000 0.01960.0522 144 −18.9 0.0074 0.0667 0.2004 145 67.4 146 −0.8 1.0568 >10 147110.5

1. A compound of Formula (I):

wherein: each R² is independently selected from the group consisting of H, halo, CN, C₁-C₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and perhaloalkoxy; n is an integer from 0-3; X is independently selected from the group consisting of H, C₁-C₃ alkyl, C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂; Y and Z are independently H or CH₃; R¹ is independently selected from the group consisting of:

R^(e) and R^(f) are H or C₁-C₃ alkyl; R^(g) is H, F, or perfluoroalkyl; R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; and R^(i) is H or halo; or pharmaceutically acceptable salts of compounds of Formula (I).
 2. A compound as defined in claim 1, wherein n is
 2. 3. A compound as defined in claim 1, wherein one R² substituent is in the ortho position.
 4. A compound as defined in claim 1, wherein one R² substituent is in the meta position.
 5. A compound as defined in claim 1, wherein n is 2, one R² substituent is in the ortho position and the other R² substituent is in the meta position.
 6. A compound as defined in claim 1, wherein n is 2, one R² substituent is in the ortho position and the other R² substituent is in the para position.
 7. A compound as defined in claim 1, wherein n is 2, one R² substituent is Cl and is in the ortho position and the other R² substituent is CF₃ and is in the meta position.
 8. A compound as defined in claim 1, wherein n is 2, one R² substituent is Cl and is in the ortho position and the other R² substituent is Cl and is in the meta position.
 9. A compound as defined in claim 1, wherein n is 2, one R² substituent is Cl and is in the ortho position and the other R² substituent is Cl and is in the para position.
 10. A compound as in defined claim 1, wherein n is 2, one R² substituent is F and is in the ortho position and the other R² substituent is Cl and is in the para position.
 11. A compound as in defined claim 1 wherein R¹ is selected from the group consisting of:


12. A compound as defined in claim 1 wherein R¹ is selected from the group consisting of:


13. A compound as defined in claim 1 wherein R¹ is:


14. A compound as defined in claim 1 wherein R^(f) and R^(g) are H and R¹ is


15. A compound as defined in claim 1 wherein X, Y, Z, R^(f) and R^(g) are H, n is 2, one R² substituent is Cl and is in the ortho position, the other R² substituent is Cl and is in the meta position and R¹ is


16. A compound as defined in claim 1 wherein Y, Z, R^(f) and R^(g) are H, X is CH₃, n is 2, one R² substituent is Cl and is in the ortho position, the other R² substituent is CF₃ and is in the meta position and R¹ is


17. A compound as defined in claim 1 wherein Z, R^(f) and R^(g) are H, X and Y are CH₃, n is 2, one R² substituent is Cl and is in the ortho position, the other R² substituent is CF₃ and is in the meta position and R¹ is


18. A compound as defined in claim 1 wherein Z, R^(f) and R^(g) are H, X and Y are CH₃, n is 2, one R² substituent is Cl and is in the ortho position, the other R² substituent is Cl and is in the para position and R¹ is


19. A compound as defined in claim 1 wherein Z, R^(f) and R^(g) are H, X and Y are CH₃, n is 2, one R² substituent is F and is in the ortho position, the other R² substituent is Cl and is in the para position and R¹ is


20. A compound selected from the group consisting of: 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 4-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-3-methylbenzonitrile; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2-Chloro-3-methylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dimethylphenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2-Chloro-3-methylphenyl)carbonyl]-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2-Chloro-4,5-difluorophenyl)carbonyl]-4-pyrazin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; (4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1-methyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2-chloro-4-fluorophenyl)carbonyl]-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine; 7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-pyridin-2-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(4-fluoro-1H-pyrazol-5-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(1,3-thiazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-2-methyl-4-[4-(trifluoromethyl)-1H-pyrazol-5-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,3-Dichlorophenyl)carbonyl]-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1,3-thiazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-isoxazol-4-yl-2-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(3,5-dimethylisoxazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Fluoro-3-(trifluoromethyl)phenyl]carbonyl}-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 2-Methyl-7-{[2-methyl-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-methyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-N,N-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; 7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-cyclopropyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; (6R)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; (6S)-7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; (4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; 3-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methylbenzonitrile; (2-chloro-3-(trifluoromethyl)phenyl)(6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-amino-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,3-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(2,6-dimethyl-4-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone; (R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone; (S)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone; (R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone; (S)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone; (2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,4-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,5-dichlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(4-chloro-2-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-4-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,4-difluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (4-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chlorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; ((R)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(2-isopropyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,4-dichloro-3-fluorophenyl)(2-ethyl-6-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (4-(1H-pyrazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone; (4-(1H-1,2,3-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone; (4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,3-dichloro-4-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; ((2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2,4-dichloro-3-fluorophenyl)(8-methyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2-chloro-3-(trifluoromethyl)phenyl)(4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-2,6-dimethyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,3-dichloro-4-fluorophenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2-chloro-3-(trifluoromethyl)phenyl)(4-(6-fluoropyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,4-dimethylphenyl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2,3-dimethylphenyl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(4-fluoro-2-methylphenyl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-fluoro-2-methylphenyl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-methylphenyl)methanone; (R)-(2,4-dichloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(phenyl)methanone; (2,4-dichlorophenyl)((6R,8S)-2,6,8-trimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone; (R*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone; (S*)-(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-(trifluoromethoxy)phenyl)methanone; (2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (R*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (S*)-(2-chloro-3-fluorophenyl)(2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone; (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(3-methoxy-2-methylphenyl)methanone; and (2,6-dimethyl-4-(1H-pyrazol-5-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(5-methoxypyridin-3-yl)methanone.
 21. A pharmaceutical composition, comprising: (a) a therapeutically effective amount of a compound of Formula (I):

wherein: each R² is independently selected from the group consisting of H, halo, CN, C₁-C₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and perhaloalkoxy; n is an integer from 0-3; X is independently selected from the group consisting of H, C₁-C₃ alkyl, C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂; Y and Z are independently H or CH₃; R¹ is independently selected from the group consisting of:

R^(e) and R^(f) are H or C₁-C₃ alkyl; R^(g) is H, F, or perfluoroalkyl; R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; and R^(i) is H or halo; or pharmaceutically acceptable salts of compounds of Formula (I); and (b) at least one pharmaceutically acceptable excipient.
 22. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 20 and at least one pharmaceutically acceptable excipient.
 23. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by P2X7 receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from compounds of Formula (I):

wherein: each R² is independently selected from the group consisting of H, halo, CN, C₁-C₃ alkyl, perhaloalkyl, C₁-C₃ alkoxy and perhaloalkoxy; n is an integer from 0-3; X is independently selected from the group consisting of H, C₁-C₃ alkyl, C₃ cycloalkyl, perfluoroalkyl, —NH₂, and —N(CH₃)₂; Y and Z are independently H or CH₃; R¹ is independently selected from the group consisting of:

R^(e) and R^(f) are H or C₁-C₃ alkyl; R^(g) is H, F, or perfluoroalkyl; R^(h) is H, C₁-C₃ alkyl, —CH₂CH₂OCH₃ or perfluoroalkyl; R^(i) is H or halo; or pharmaceutically acceptable salts of compounds of Formula (I).
 24. The method as defined in claim 23, wherein the disease, disorder or medical condition is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, psoriasis, septic shock, allergic dermatitis, asthma, allergic asthma, mild to severe asthma, steroid resistant asthma, idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease; airway hyper-responsiveness, diseases of the nervous and neuro-immune system, acute and chronic pain states of neuropathic pain, inflammatory pain, spontaneous pain, opioid induced pain, diabetic neuropathy, postherpetic neuralgia, low back pain, chemotherapy-induced neuropathic pain, fibromyalgia, diseases involved with and without neuroinflammation of the central nervous system, mood disorders, major depression, major depressive disorder, treatment resistant depression, bipolar disorder, anxious depression, anxiety, cognition, sleep disorders, multiple sclerosis, epileptic seizures, Parkinson's disease, schizophrenia, Alzheimer's disease, Huntington's disease, autism, spinal cord injury and cerebral ischemia/traumatic brain injury, stress-related disorders, diseases of the cardiovascular, metabolic, gastrointestinal and urogenital systems such as diabetes, diabetes mellitus, thrombosis, irritable bowel syndrome, irritable bowel disease, Crohn's disease, ischemic heart disease, ischaemia, hypertension, cardiovascular disease, myocardial infarction, and lower urinary tract dysfunction such as incontinence, lower urinary tract syndrome, Polycystic Kidney Disease, Glomerulonephritis, skeletal disorders, osteoporosis, osteopetrosis, and glaucoma, interstitial cystitis, cough, ureteric obstruction, sepsis, Amyotrophic Lateral Sclerosis, Chaga's Disease, chlamydia, neuroblastoma, Tuberculosis, and migraine.
 25. The method of as defined in claim 24, wherein the disease, disorder or medical condition is treatment resistant depression. 